Cr 013 presentation sporanox® by carolina hung ho

AAPS College (Toronto Canada)

Clinical Pharmacology and Safety Assessments Presented

by Carolina Hung Ho

Professor Dr Peivand Pirouzi

Peer-reviewed by TBD

May 05 2016

Proposed New Indication for

Itraconazole (Sporanoxreg) in

Treatment of Cancer

Outline

Introduction

Pharmacokinetics

Absorption

Distribution

Metabolism

Elimination

Pharmacodynamics

CYP-450-dependent Inhibition of

Ergosterol Synthesis

Drug and Drug Interactions

Drug and Food Interactions

Adverse Drug Reactions

Pharmacogenomics

Special Population

Proposed New Indication Anti-

Cancer Properties

Proposed Mechanisms for

Anti-cancer activity

Cyclodextrins

Challenges

Conclusions

References

Question Session

Introduction

Itraconazole (ITZ) is used to treat many fungal infections

Invented in 1984

Marketed under several brand names

Janssen Pharmaceuticals a subsidiary of Johnson amp Johnson is marketing the drug under the brand name Sporanoxreg

Available as

100 mg capsule

10 mgmL oral suspension

Prescription only

IV formulation is not available in the USA or CAD

DIN 02047454

(Canada 1993)

DIN 02231347

(Canada 1997)

Chemical Information

Proper name Itraconazole

A synthetic triazole derivative

Chemical name(plusmn)-cis-4-[4-[4-[4-[[2-(24-dichlorophenyl)-2-(1H-124-triazol-1- ylmethyl)-13-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-24-dihydro-2-(1-methylpropyl)-3H-124- triazol-3-one

Structural formula

Lipophilic molecule

pKa = 37

Log partition coefficient in octanolwater = 82

Figure 1 Chemical Structure of Itraconazole (Janssen 2015)

Approved Indications

SPORANOXreg capsules (100 mg)

1 Invasive and non-invasive pulmonary aspergillosis

2 Oral andor esophageal candidiasis

3 Chronic pulmonary histoplasmosis

4 Cutaneous and lymphatic sporotrichosis

5 Paracoccidioidomycosis

6 Chromomycosis

7 Blastomycosis

8 Dermatomycosis

9 Onychomycosis

Systemic fungal

infections

Topical fungal

infections

Approved Indications (Contrsquod)

Systemic fungal

infections

Topical fungal

infections

Fig 21 Photomicrograph

of Asperlligus fumigatusFig 22 Photomicrograph

of Candida albicans


of DermatocomysesFig 24 Onychomycosis

affects the nails


SPORANOXreg oral solution (10 mg mL)


bull SPORANOXreg is safe for use in normal predisposed or immunocompromised

adult patients (eg HIV-positive)

bull SPORANOXreg oral solution and SPORANOXreg capsules should not be used

interchangeably

bull For use in special populations see Special Populations

Pharmacokinetics

Absorption

Oral bioavailability of SPORANOXreg capsules is maximal when

taken immediately after a full meal (Added excipient sugar

spheres)

Oral bioavailability of SPORANOXreg oral solution is maximal

when taken without food (Added excipient hydroxypropyl-β-

cyclodextrin)

Table 1 Pharmacokinetic data on Itraconazole from a

randomized cross-over study on 7 healthy male subjects

following administration of an oral solution

Plasma clearance rate = 381 plusmn 95 mLmin

Volume of distribution = 796 plusmn 185 L

Oral bioavailability = 33 - 55 (variable)

Pharmacokinetics

Absorption

ITZ exposure is lower with the capsule

formulation than with the oral solution when

the same dose of drug is given

Gastric acidity = Absorption

Can be caused by medications (eg H2

receptor agonists and proton pump inhibitors)

Can be caused by certain diseases (eg

achlorhydria)

Non-diet Cola can help to absorb ITZ

under fasted conditions

Fig 3 Bioavailability of

itraconazole in two capsule

and one oral formulation

among 60 healthy volunteers

(Barone et al 1998)

Pharmacokinetics (Contrsquod)

Distribution

The plasma protein binding of ITZ is 998 and that of

hydroxy-ITZ is 995

ITZ is extensively distributed into tissues which are

prone to fungal infection

Lung

Kidney

Bones

Stomach

Spleen

Muscle

Skin Cskin is 5X higher than Cplasma

Ctissues is 2X times than Cplasma


Metabolism

Extensive metabolism by the liver

Major enzyme CYP 3A4

Main metabolite Hydroxy-itraconazole (OH-ITZ)

Same antifungal effect efficacy maintained

Present 3x higher in the tissues (HPLC)

Shorter T12 of elimination

gt 30 other metabolic pathways involved


Hydroxylation ndash adding ndashOH

Reaction By CYP 3A4-body attempt to make compound

more polar for conjugation and

easier to eliminate


Elimination

The feces (18 as active drug 54 as inactive

metabolites )

Active transport in the bile

Using oral radiolabelled dose to track its fate

The urine (lt 003 active drug 35 as inactive

metabolites)


Fig 5 The fate of Itraconazole in the human

body

Half-Life (T12) Elimination

Single dose 16 to 28 hours

Multiple doses 34 to 42

hours

Cirrhotic (single dose) 37

hours

Mode of Action

ITZ Inhibits P450 lanosterol 14-demethylase

Enzyme responsible for converting lanosterol ergosterol

Ergosterol is needed for cell membrane fluidity amp stability

Without ergosterol cell membrane is disrupted

Fungi are unable to grow and divide

Fig 6 Structure of P450

lanosterol 14-demythalase

(Podul et al)

Mode of Action

Fig 7 Cell membrane and cell wall structure of a fungal cell

Drug-Drug Interactions

ITZ (and its metabolites) are potent CYP 3A4 inhibitors

By competing with other substrates for CYP 3A4 binding sites in

liver hepatocytes

ITZ is a potent P-glycoprotein (P-gp) inhibitor

By competing with other substrates for P-g binding sites in the

liver kidney endothelium and brain

Pg is responsible for active transport drugs back into the gut

lumen or into the bile

RESULT May alter Cp of other drugs or other drugs

may alter Cp of ITZ

Prolonged therapeutic effects or overdose of these drugs

Therefore many drugs are contraindicated with SPORANOXreg

a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen

Drug Contraindications

Refer to Product Monograph for Itraconazole for a

list of contraindicated medications

bull CONTRAINDICATED (Table 1)

bull May increase risks of serious cardiovascular events (eg

QT prolongation Torsade de pointes bleeding etc)

bull NOT RECOMMENDED (Table 2)

bull If co-administration cannot be avoided consider monitoring

signs symptoms plasma levels of ITZ dose adjustment

etc

bull USE WITH CAUTION (Table 3)

bull Interaction is not well established

bull Monitoring required

bull Special populations

Food-Drug Interactions

Grapefruit juice is also a CYP 3A4

inhibitor

The culprit furanocomarins

It may

1 May reduce or raise Cp of ITZ

2

Therefore grapefruit juice is NOT

recommended when taking

SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions

Rare and serious Hepatotoxivity Acute liver

failure and death

Common ADRs GI origin (dyspepsia nausea

vomiting diarrhea abdominal pain and constipation)

Overdosage No experience with overdosage

If suspected treated with activated charcoal

ITZ cannot be removed through hemodialysis

Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics

In vitro studies (cultured cells)

[ITZ] = 4 x 10-7M 50 inhibition of cholesterol biosynthesis in human lymphocytes

[ITZ] = 4 x 10-5M 50 inhibition of ergosterol in Candida albicanscells

Point 1 ITZ is selectively toxic to fungal cells

Phase I (healthy volunteers)

100 mg ITZ od for 1 month no difference in basal serum cholesterol levels between control and treatment groups

50 - 400 mg ITZ od for max 2 years basal serum cholesterol were not significantly affected in 3 studies

Point 2 Short and long-term exposure to ITZ does not significantly affect cholesterol levels in human

Note

Your Total Blood (or

Serum) Cholesterol

Your total cholesterol

score is calculated by

the following equation

HDL + LDL + 20 of

your triglyceride level A

total cholesterol score

of less than 180 mgdL

is considered optimal

Pharmacodynamics


100 mg or 200 mg daily for 1 month no significant change in hormone levels

CNS (eg LH FSH prolactin)

Reproductive organs (eg estrogen testosterone)

Adrenal gland (eg cortisol)

Point 3 ITZ does not cross BBB into cerebrospinal fluid (cannot reach your brain)

200 mg daily for 5 weeks no significant effect on the HR BP ECG-intervals in health volunteers

Point 4 ITZ does not affect the cardiovascular system

200 mg daily for 5 weeks no negative effect on immune functions Values for OKT4 positive lymphocyte showed a significant shift from 42 plusmn 33 to 53 plusmn33 This increase as well as shifts in the other immunological parameters remained within the normal ranges

Point 5 ITZ does not affect immune system

Pharmacodynamics

In summary

Safe for human does not affect cholesterol levels

Does not adversely affect the brain the heart or the immune system

directly Exception Rare cases of CHF

Precautions must be taken however when co-administered with

other medications and grapefruit juice

But what about the kidney and the liver

See ldquoWarnings and Precautionsrdquo

See ldquoDrug Interactionsrdquo

Special Population

Geriatrics (gt 65 years of age)

Use caution

Use only when potential benefit outweighs the

potential risks

Pediatrics (lt 18 years of age)

The efficacy and safety of SPORANOXreg have not yet

been established

Use caution

Special Population

Pregnant Women and Lactating Mothers

Should not be used if pregnant or planning pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the fetus

For women of childbearing age SPORANOXreg should not be prescribed unless effective contraception methods are used prior to the start of therapy

Nursing Women

Itraconazole is excreted in human milk therefore the patient should be advised to discontinue nursing while taking SPORANOXreg

Special Population

Impaired renal function

Limited data available Exercise caution

ITZ is mainly excreted through the feces so BA is slightly increased if kidney function is impaired

Impaired liver function


Cmax was reduced by 47 and resulted in a twofold increase in half-life (capsules)

ITZ is extensively metabolized by the liver so impaired liver function (eg cirrhosis liver failure) elevate BA of other drugs overdose + toxicity

Pharmacodynamics (Contrsquod)

Efficacy amp Safety

Large Vdistrsquon

Long T12

Main metabolite works just as

well as the parent drug

Precaution taken with

Concomitant medications

Liver or kidney failure

History of CHF

Special populations

Fig 9 Plasma concentrations of

Itraconazole and its metabolite

hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug

Current Indication Proposed Indication

Use as prophylactic agent

andor as part of

chemotherapy

Fights off infections caused

by many fungal species

Why Choose Sporanoxreg

Shown to have anti-neoplastic effects in vitro and in vivo pre-clinical trials

2 Proposed Mechanisms

1 Block the angiogenesis pathway

2 Block the Hedgehog signaling pathway

Types of cells studied

Basal cell carcinoma

Non-small lung cancer cells

Prostrate cancer cells

Breast cancer cells

Long and well established safety profile

An affordable and accessible generic drug


Phase II Trial

A Randomized Phase II Clinical Trial of Two Dose-levels of

Itraconazole in Patients With Metastatic Castration-resistant

Prostate Cancer

Identifier NCT00887458

Sponsor Johns Hopkins University

Collaborator Memorial Sloan Kettering Cancer Center

Start date July 2009

End date December 2013

Phase II Study

Investigational drug Itraconazole

Condition Prostrate Cancer

Study type Efficacy

Duration 24 weeks (6 months)

N= 42 patients

Treatment

Group Treatment Total daily

dose

Low dose 200 mg by mouth once daily 200 mg

High dose 300 mg by mouth twice daily 600 mg

Phase II Study (Contrsquod)

Results

1 Efficacy

PSA ndash Prostrate Specific Antigen are secreted by prostrate tumour cells serve as tumour markers

PSA progression is defined as a 25 increase in PSA over baseline or a 2 ngml increase when confirmed again 4 weeks later

Conclusion High dose ITZ (600mgday) significant PSA responses and delay in tumour progression

Group Total daily dose Subjects No PSA Progression at

24 weeks (95 CI)

Low dose 200 mg 17 11

High dose 600 mg 25 48


Results

2 Safety ndash Adverse Events

Type of AE AE Low dose High dose

Serious Fatigue 6 0

Other events (5) Hypertension

Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations

Small sample size N=42 patients

Advanced stages of prostrate cancer

AEs ndash no causality established yet

Anti-cancer Properties of

Itraconazole

Figure 10 Proposed Mechanisms for Anti-cancer activity1) Blocking the

Signal in the Hedgedog Pathway and 2) Blocks Angiogenesis (King 2015)

Blocking the Angiogenesis

Pathway Sporanoxreg

Angiogenesis describes the process why which new blood vessels grow

Cancer cells need blood vessels to grow and metastasize

Cancer cells grow their vessels by releasing angiogenic growth factor proteins (eg VEGH)

ITZ has been shown to block this pathway in cancer cell lines by inducing inhibitory factors

Hope to see that it can also stop cancer cells from growing vessels in humans


Pathway Sporanoxreg

Watch Video httpswwwyoutubecomwatchv=hVYdV3wKg-k

Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)

Blocking the Hedgehog Signaling

Pathway Sporanoxreg

LINK httpswwwyoutubecomwatchv=gFWO3I-oqsE

Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg

Hedgehog signaling pathway is essential for

embryonic development remains active in adult

tissues

Involve proteins that control cell proliferation

differentiation and tissue patterning

Over-stimulation of this pathway has been linked to

cancer of the brain GI lung breast and prostrate

gland

ITZ has shown to inhibit this signaling pathway thus

slowing cancer progression

Challenges for Sporanoxreg

Challenge 1 Varied bioavailability

Capsule 6-20

Oral Solution 20-60

2-(HYDROXYPROPYL)-BETA-CYCLODEXTRIN

An excipient in oral solution and IV formulation

Used to improve water solubility rate of dissolution

and hence its bioavailability

By forming a complex with drug molecule

Lipophilic cavity ndash holds ITZ

Hydrophobic exterior


Excipient 2-(HYDROXYPROPYL)-BETA-CYCLODEXTRIN

In the 1996 Horsky et al From National Institute of Health (NIH) indicated

that

ldquoHP-B-Cyclodextrin when used in pharmaceutical formulations has potential

to increase the absorption of carcinogens which enter the GI tract as food

components or from air pollutionrdquo

Note The author cautions against the use of very large quantities of the

substance because if it can enhance BA of a therapeutic drug it can also

provide the same service for harmful chemicals


Safety

For oral high doses (gt 1000 mgkgday)

Diarrhea

Enlargement of faeces seen only in animals

For IV high doses

nephrotoxicity in animal studies seen only in animals

At present it is not required to add information on these excipients in the

package leaflet of medicinal products (European Union 2015)

The presence of cyclodextrins should always be stated as a precaution

because of limited information and possible interaction with

active substances


Fig 14 Chemical structure of

hydroxypropyl-beta-cyclodextrin and

formation of inclusion complex with

lipophilic molecule such as ITZ

(European Union 2015)

Pharmacokinetic Properties of

Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None

Excretion Oral ndash faeces

IV ndash kidney

GRAS ndash generally recognized as safe

Maximum Daily Intake 8000 mgday

Estimated Dose from Sporanox

~160 mgday

Improving its Bioavailability

Nanosizing - to reduce the particle size of the ITZ to sub-micron range typically between 100-200nm to enhance its oral bioavailability

Mechanism Maximizing surface area to improve its dissolution rate which in turn enhances its bioavailability

Require the use of stabilizers (eg polymers)

Examples

1 High Pressure Homogeneous

2 Supercritical Fluid Process


Fig 15 Scanning electron

microscopy micrographs

of coarse itraconazole

powders (top) and

lyophilized intraconazole

nanocrystals by

homogenized high

pressure (Sun et al (2011)

Nanotechnology Enhancing

Bioavailability of Itraconazole

Figure 16 Using nanotechnology modify Itraconazole using silica into flakes The goal is to

increase the rate of dissolution of ITZ in the stomach thus increasing absorption rate by

the body


Challenge 2 Potential Drug to Drug Interactions

with Other Anti-neoplastic Drugs

Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments

irinotecan CONTRAINDICATED The potential increase in plasma concentrations of irinotecan

when coadministered with SPORANOXreg may increase the risk of potentially fatal adverse

events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma

levels of these drugs 1113089

NOT RECOMMENDED It is recommended that the use of these drugs be avoided

during and up to 2 weeks after discontinuation of treatment with itraconazole unless the

benefits outweigh the potentially increased risks of side effects If coadministration cannot

be avoided clinical monitoring for signs or symptoms of increased or prolonged effects or

side effects of the interacting drug is recommended and its dosage be reduced or

interrupted as deemed necessary When appropriate it is recommended that plasma

concentrations be measured

bortezomib busulphan

docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib

ponatanib trimetrexate

vinca alkaloids

May increase plasma


USE WITH CAUTION Careful monitoring is recommended when these drugs are

coadministered with itraconazole Upon coadministration it is recommended that patients

be monitored closely for signs or symptoms of increased or prolonged effects or side

effects of the interacting drug and its dosage be reduced as deemed necessary When

appropriate it is recommended that plasma concentrations be measured See 3 above for

further information


Challenge 2 Potential Drug to Drug Interactions with Anti-neoplastic Drugs

Antineoplatic Drugs Tested In-Vitro So Far

1 Pemetrexed

At 3 months 67 of the patients on itraconazole plus pemetrexed were progression-free versus 29 on the control arm of pemetrexed alone (p = 011) (Rudin et al 2013)

2 Cinsplastin

Itraconazole and Itraconazole plus Cisplatin has shown significant reduction in endothelial cell proliferation migration and tube formation in response to angiogenic stimulation from non-small cell cancer lines (Afba et al 2011)

Fig 17 Survival rate of small cancer

cell lines exposed to permetrexed +

itraconacole vs permetrexed alone

(Rudin et al 2013)

Positive Outlook

According to National Institute of Cancer Research

there are over 200 anticancer drugs availablehellip

ANDhellip

Itraconazole has been shown to have potential drug-to

drug interactions with only 20 or so of these drugs

There are still 180 drugs from which Itraconazole can be

integrated as a part for cancer chemotherapy

Conclusions

ITZ should be further considered for its potential anticancer effects

Long record of safety

In-vitro and early phase clinical trials showcases consistent anti-cancer effects

But must take into consideration

Limited applicability in clinical practice due to its wide range of interactions with other drugs

Angiogenesis and Hedgehog signaling pathways are not well understood ndash more research

Explore alternatives for enhancing its availability

How to incorporate this new drug into a chemotherapy regime ndash Diarrhea is the common side effects

References

(2014) Background review for cyclodextrins used as excipients CPMP46300 Rev 1 European Medicines Agency httpwwwemaeuropaeudocsen_GBdocument_libraryReport201412WC500177936pdf

Barone J Moskovitz B Guarnieri B Hassell A Colaizzi J Bierman R amp Louis J (1998) Enhanced Bioavailability of Itraconazole in Hydroxypropylβ-Cyclodextrin Solution versus Capsules in Healthy Volunteers American Society of Microbiology 42 (7) 1862-1865

Carducci M (2014) A Two-dose Level Clinical Trial of Itraconazole in Patients With Metastatic Prostate Cancer Who Have Had Disease Progression While on Hormonal Therapy National Institute of Health Clinicaltrialsorg Identifier NCT00887458 httpsclinicaltrialsgovct2showresultsNCT00887458sect=X70156ampterm=sporanoxamprank=27outcome1

Diamond R (1999) Atlas of Fungal Infections Introduction to Medical Mycology Merck and Co

Du R Lu K V Petritsch C Liu P Ganss R Passegueacute E hellip Bergers G (2008) HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and Invasion Cancer Cell 13(3) 206ndash220 httpdoiorg101016jccr200801034

Horsky J Pitha J (1996) Hydroxypropyl cyclodextrins potential synergism with carcinogens Journal of Pharmaceutical Science 85(1) 96-100 httpwwwncbinlmnihgovpubmed8926593

McMillan R Matsui W (2012) Molecular Pathways The Hedgehog Signaling Pathway in Cancer American Association for Cancer Research 18(18) 4883ndash4888 httpclincancerresaacrjournalsorgcontent18184883fullpdf+html

References (Contrsquod)Nanonization of Itraconazole by High Pressure Homogenization Stabilizer Optimization Podust LM von Kries JP Eddine AN Kim Y

et al Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-ray

Crystallography Antimicrob Agents Chemother 2007 51(11) 3915-23

Pantziarka P Sukhatme V Bouche G Meheus L amp Sukhatme V P (2015) Repurposing Drugs in Oncology (ReDO)mdash

itraconazole as an anti-cancer agent Ecancermedicalscience 9 521 httpdoiorg103332ecancer2015521

Product Monograph PrSPORANOXreg itraconazole oral solution 10 mgmL Antifungal Agent (2015) Janssen Inc Extracted

from Health Canada Drug Directorate DIN number 02047454

Product Monograph PrSPORANOXreg itraconazole capsules 100 mg Antifungal Agent (2015) Janssen Inc Extracted from

Health Canada Drug Directorate DIN number 02231347

Rudin Charles M et al (2013) Phase 2 Study of Pemetrexed and Itraconazole as Second-Line Therapy for Metastatic

Nonsquamous NonndashSmall-Cell Lung Cancer Journal of Thoracic Oncology 8 (5) 619 ndash 623 httpwwwjtoorgarticleS1556-

0864(15)32820-3abstract

Stella V J He Q (2008) Cyclodextrins Toxicologic Pathology 36(1) 30-42

httptpxsagepubcomcontent36130long

Sun W Mao S Shi Y Li L Fang L (2011) Journal of Pharmaceutical Sciences 100 (8) 3365-3373

httpjpharmsciorgarticleS0022-3549(15)32030-Xpdf

Types of Fungal Diseases (2014 December 04) Retrieved April 04 2016 from httpwwwcdcgovfungaldiseasesindexhtml

Thank You The statements opinions and data contained in this publication are

solely those of the individual Authors and contributors for academic

purposes and do not reflect the opinion of the company that markets

the product(s)

Outline

Introduction

Pharmacokinetics

Absorption

Distribution

Metabolism

Elimination

Pharmacodynamics

CYP-450-dependent Inhibition of

Ergosterol Synthesis

Drug and Drug Interactions

Drug and Food Interactions

Adverse Drug Reactions

Pharmacogenomics

Special Population

Proposed New Indication Anti-

Cancer Properties

Proposed Mechanisms for

Anti-cancer activity

Cyclodextrins

Challenges

Conclusions

References

Question Session

Introduction


Invented in 1984



Available as

100 mg capsule


Prescription only


DIN 02047454

(Canada 1993)

DIN 02231347

(Canada 1997)





Structural formula

Lipophilic molecule

pKa = 37










6 Chromomycosis

7 Blastomycosis

8 Dermatomycosis

9 Onychomycosis

Systemic fungal

infections

Topical fungal

infections


Systemic fungal

infections

Topical fungal

infections



of Candida albicans



affects the nails







interchangeably


Pharmacokinetics

Absorption



spheres)



cyclodextrin)







Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Introduction


Invented in 1984



Available as

100 mg capsule


Prescription only


DIN 02047454

(Canada 1993)

DIN 02231347

(Canada 1997)





Structural formula

Lipophilic molecule

pKa = 37










6 Chromomycosis

7 Blastomycosis

8 Dermatomycosis

9 Onychomycosis

Systemic fungal

infections

Topical fungal

infections


Systemic fungal

infections

Topical fungal

infections



of Candida albicans



affects the nails







interchangeably


Pharmacokinetics

Absorption



spheres)



cyclodextrin)







Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)





Structural formula

Lipophilic molecule

pKa = 37










6 Chromomycosis

7 Blastomycosis

8 Dermatomycosis

9 Onychomycosis

Systemic fungal

infections

Topical fungal

infections


Systemic fungal

infections

Topical fungal

infections



of Candida albicans



affects the nails







interchangeably


Pharmacokinetics

Absorption



spheres)



cyclodextrin)







Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)








6 Chromomycosis

7 Blastomycosis

8 Dermatomycosis

9 Onychomycosis

Systemic fungal

infections

Topical fungal

infections


Systemic fungal

infections

Topical fungal

infections



of Candida albicans



affects the nails







interchangeably


Pharmacokinetics

Absorption



spheres)



cyclodextrin)







Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Systemic fungal

infections

Topical fungal

infections



of Candida albicans



affects the nails







interchangeably


Pharmacokinetics

Absorption



spheres)



cyclodextrin)







Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)







interchangeably


Pharmacokinetics

Absorption



spheres)



cyclodextrin)







Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Pharmacokinetics

Absorption



spheres)



cyclodextrin)







Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Pharmacokinetics

Absorption








achlorhydria)







(Barone et al 1998)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Distribution


hydroxy-ITZ is 995



Lung

Kidney

Bones

Stomach

Spleen

Muscle




Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Metabolism












easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)





easier to eliminate


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Elimination


metabolites )




metabolites)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)



body




hours


hours

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Mode of Action








(Podul et al)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Mode of Action





liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)




liver hepatocytes







may alter Cp of ITZ



a long list

eg ITZ may

elevate morphine

plasma

concentrations

possibly by

inhibiting P-g

elimination of

morphine into gut

lumen










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)










etc







inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)



inhibitor


It may


2



SPORANOXreg

Fig 8 Furanocomarin

in Grapefruit juice

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Adverse Reactions


failure and death






Other toxicity

Mutagenicity NO

Teratogenicity NO

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Pharmacodynamics









Note


Serum) Cholesterol




HDL + LDL + 20 of





Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Pharmacodynamics











Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Pharmacodynamics

In summary









Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Special Population


Use caution


potential risks



been established

Use caution

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Special Population




Nursing Women


Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Special Population









Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Efficacy amp Safety

Large Vdistrsquon

Long T12






History of CHF

Special populations



hydroxyitraconazole


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Sporanoxreg

Fungal

Infections

Anti-Cancer

Drug



andor as part of

chemotherapy












Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)










Breast cancer cells




Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Phase II Trial



Prostate Cancer






Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Phase II Study



Study type Efficacy


N= 42 patients

Treatment


dose




Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Results

1 Efficacy





24 weeks (95 CI)




Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Results



Serious Fatigue 6 0


Anorexia

Fatigue

Hypokalemia

Rash

-

11

52

-

18

31

17

20

17

7

Limitations





Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Itraconazole




Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Pathway Sporanoxreg







Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Pathway Sporanoxreg


Fig 11

Angiogenesis

and Tumour

Metastasis The

search for

drugs that

inhibit this

hallmark of

cancer

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Figure 12

Itraconazole and

Itraconazole plus

Cisplatin (an

approved

chemotherapeutic

drug) has shown

significant

reduction in

endothelial cell

proliferation

migration and

tube formation in

response to

angiogenic

stimulation from

non-small cell

cancer lines

(Afba et al 2011)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Pathway Sporanoxreg


Fig 13 The

hedgehog

signaling

pathway and

overstimulati

on in tumour

cells


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Pathway Sporanoxreg



tissues





gland





Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)



Capsule 6-20

Oral Solution 20-60











that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)




that








Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)


Safety


Diarrhea


For IV high doses






active substances








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)








Hydroxypropyl-beta-

cyclodextrin

Absorption Poor

Distribution

Bioavailability

None

0-3

Metabolism None


IV ndash kidney




~160 mgday





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)





Examples







powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)





powders (top) and


nanocrystals by

homogenized high






the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)





the body




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)




Antineoplastic

Drugs

Coadministration

with Sporanox

Clinical Comments



events

axitinib

dabrafenib

dasatinib

ibrutinib

nilotinib

sunitinib

trabectedin

May increase plasma










docetaxel

erlotinib

gefitinib

imatinib

ixabepilone

lapatinib


vinca alkaloids

May increase plasma







further information




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)




1 Pemetrexed


2 Cinsplastin





(Rudin et al 2013)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Positive Outlook



ANDhellip





Conclusions









References



















0864(15)32820-3abstract









the product(s)

Conclusions









References



















0864(15)32820-3abstract









the product(s)

References



















0864(15)32820-3abstract









the product(s)












0864(15)32820-3abstract









the product(s)




the product(s)

Health & Medicine

Cr 013 presentation sporanox® by carolina hung ho