DEVELOPING FLUBENDAZOLE FOR USE AS A MACROFILARIACIDE IN

FILARIASIS

OBJECTIVE 3. DOLF

FLUBENDAZOLE

• Binds to tubulin –preferentially to nematode tubulin over mammalian tubulin

• A benzimidazole – as a group it has a good track record for safety…..e.g. albendazole, etc.

• Licensed in Europe for intestinal helminth Rx

WHY FLUBENDAZOLE?

• ANIMAL STUDIES – Brugia in jirds – effective in a single dose

– Dirofilaria – effective in a single parenteral dose

– Has poor/no microfilariacidal effect

– Maybe has some prophylactic action (in Brugia)

• HUMAN STUDIES – Registered for use as an intestinal anthelminthic

– Mexico 1982 studies

(1983) An unpublished additional study – Mackenzie and Martinez-Palomo

FLUBENDAZOLE STUDIES IN CHIAPAS MEXICO 1981-1983

THIS STUDY HAD PROBLEMS WITH THE INJECTION SITE ABSCESSES

THE EFFECT OF FLUBENDAZOLE ON ADULT ONCHOCERCA VOLVULUS COMPARED WITH DIETHYLCARBAMAZINE

SAEs DURING FIRST 2 MONTHS OF THERAPY DEC (n= 9) FLUBENDAZOLE (n=8)

PRURITUS 9 0

RASH 9 0

LYMPHADENOPATHY 9 0

ANOREXIA 8 1

DIZZINESS 6 2

HEADACH 7 3

FEVER 8 7

INFLAMMATION AT SITE 0 8

EFFECT ON MICROFILARIAE Dominguez et al, 1983

MONTH 0 0.25 1 2 3 6 9 12

DEC 101 1 2 4 8 9 3 9

FLUB 21 31 35 31 4 >1 >1 0

MAJOR OPHTHALMOLOGIC COMPLICATIONS DURING THERAPY

DIETHYLCARBAMAZINE (n=9)

FLUBENDAZOLE (n=8)

LIMBITIS 8 0

PUNCTATE KERATITIS

9 1

UVEITIS 5 0

RETINAL PIGMENT EPITH ATROPHY

1 0

SOLUBILITY STUDIES PFIZER-MSU STUDY 2008

• COMPARED A STANDARD RANGE OF SOLUBILIZING EXCIPIENTS

• THE OPTIMAL SOLUBILIZING AGENT WAS PROPYLENE GLYCOL 40:60

DOMINOWSKI & MACKENZIE 2008

EXPERIMENTAL MODELS

• ORAL FORMULATION EFFECTIVE FOR TISSUE PARASITES (CYSTICERCOSIS) – LANUSSE et al.

• USERS DO NOT REPORT ANY TOXPATH ISSUES

HYDROXYPROPYL-β-CYCLODEXTRIN

OBJECTIVE 3 - DOLF

1. REVIEW THE LITERATURE

2. CONTACT RESEARCHERS & PHARMACEUTICAL PERSONNEL

3. DEVELOP A NEW B&M GATES PROPOSAL FOR NEW FUNDING

4. BEGIN PK/PD AND EFFICACY STUDIES WITH βCD FLUBENDAZOLE

5. COMPLETE A REPORT (DOSSIER) ON 1, 2 & 4

REVIEW OF LABORATORY MODELS Lowest dose used that was effective Range 1.5 – 100 mg/kg

THE EARLY DISCUSSIONS

• FOUND NO LIMITING ISSUES

• HAD MUCH SUPPORT AND INTEREST FROM A NUMBER OF MAJOR PHARMACUETICAL COMPANIES

• DNDi BECOMES THE LEAD PARTNER FOR THE SECOND STAGE GRANT (AIMING AT AN IND)

DOCUMENTATION

EXPERT REV ANTI INFECT THER 9 (5) 497-501 (2011)

OBJECTIVE 3 - DOLF

1. REVIEW THE LITERATURE - DONE (+ PUB)

2. CONTACT RESEARCHERS & PHARMACEUTICAL PERSONNEL - DONE

3. DEVELOP A NEW B&M GATES PROPOSAL FOR NEW FUNDING – DONE AND FUNDED

4. BEGIN PK/PD AND EFFICACY STUDIES WITH βCD FLUBENDAZOLE - UNDERWAY

5. COMPLETE A REPORT (DOSSIER) ON 1, 2 & 4 – DUE JAN 2012

PK-PD STUDIES WITH β CD

• CARLOS LANUSSE – TANDIL, ARGENTINA – RATS, JIRDS AND PIGS

• Flubendazole-hydropropyl-β-cyclodextrin – FBLZ-HPBCDoral

– FLBX-HPBCDsc

• Flubendazole-carboxymethyl cellulose – FLBZ-CMC (oral)

Experimental Design Species

• Rats and Jirds – Each formulation group n=44 – 5mg/kg dose rate – Blood plasma evaluated by HPLC

• Pre-treatment and 5, 15 & 30 minutes and 1,2,3,4,6,8, & 16 hours post treatment

• Pigs – Each formulation group n=4 – 2mg/kg dose rate – Blood plasma evaluated by HPLC

• Pre-treatment and 1,3,6,9,12,15,24, 48 & 54 hours post treatment

Pharmacokinetics

• HPLC analysis of blood plasma for Flubendazole and it’s metabolites:

– Flubendazole(FLBZ)

– Reduced-Flubendazole (R-FLBZ)

– Hydrolyzed-FLBX (H-FLBZ)

– Oxibendazole (internal standard)

Plasma concentration profiles Rats

0 2 4 6 8 10 12

0,0

0,5

1,0

1,5

2,0

2,5

3,0

FLBZ. AUC= 4.8 ± 0.8 µg.h/mL

H-FLBZ. AUC= 4.3 ± 1.3 µg.h/mL

R-FLBZ. AUC= 0.9 ± 0.1 µg.h/mL

FLBZ-HPBCD (oral)

Pla

sm

a c

on

ce

ntr

atio

n (

µg/m

L)

Time (h)

Plasma concentration profiles Rats

-2 0 2 4 6 8 10 12 14 16

0,0

0,3

0,6

0,9

1,2

1,5

1,8

FLBZ. AUC= 7.3 ± 0.6 µg.h/mL

H-FLBZ. AUC= 5.1 ± 0.7 µg.h/mL

R-FLBZ. AUC= 1.4 ± 0.1 µg.h/mL

FLBZ-HPBCD(SC)

P

lasm

a c

on

ce

ntr

atio

n (

µg

/mL

)

Time (h)

Plasma concentration profiles Rats

0 2 4 6 8 10 12

0,00

0,04

0,08

0,12

0,16

0,20

FLBZ. AUC= 0.9 ± 0.1 µg.h/mL

H-FLBZ. AUC= 0.5 ± 0.2 µg.h/mL

R-FLBZ. AUC= 0.2 ± 0.1 µg.h/mL

FLBZ-CMC

Pla

sm

a c

on

ce

ntr

atio

n (

µg

/mL

)

Time (h)

Pharmacokinetic Parameters Rats

Plasma concentration profiles Jirds

0 2 4 6 8 10

0,0

0,5

1,0

1,5

2,0

2,5

3,0FLUBENDAZOLE

Pla

sm

a c

on

ce

ntr

atio

n (

µg

/mL

)

Time (h)

FLBZ-HPBCD (sc)

FLBZ-HPBCD (oral)

Pharmacokinetic Parameters Jirds

Conclusions

• Flubendazole metabolic patterns and relative systemic exposure of the parent flubendazole and its metabolites differ among species.

• Flubendazole pharmacokinetic behavior can be markedly improved by changing the formulation

• The alterations in systemic exposure to flubendazole obtained with the cyclodextrin formulation (both oral and parenteral) is likely to have a great impact on clinical efficacy.

THE NEXT STAGE

B&M Gates Grant II

PHASE 2

• LED BY DNDi (Rob Don and Ivan Scandale)

• A “DEVELOPING” MULTI-COMPONENT TEAM

– REFORMULATION - Abbott (Chicago)

– PK/PD & Efficacy & Safety – MSU/McGill

– SAFETY – UNI CARDIFF & OTHERS

– PRODUCTION ISSUES - ?

- PLANNING FOR FIELD STUDIES - ?

TIMING OF PROJECT

DNDi- ABBOTT unpublished

Formulation Update

• Nanosuspension vs. cyclodextrin vs. solid dispersion

– All three formulations provided comparable exposure at low dose (2 mg/kg)

– Amorphous solid dispersion provided highest exposure, with lowest variability, at 20 mg/kg

• High variability with cyclodextrin formulation

• Lowest exposure with nano-suspension formulation

• Further dose escalation is not possible with cyclodextrin formulation (solubility limited to ~2 mg/ml)

• Solid dispersion formulation administered to rats at higher doses (50, 100 mg/kg) to profile dose response (analysis in progress)

Presentation Title Date

31

ADME preliminary results Absorption, Distribution, Metabolism and Excretion

• Stable in vitro (microsomes, hepatocytes)

• Modest protein binding

• High permeability

• Low potential for drug-drug interactions (as inhibitor)

Presentation Title Date

32 Company Confidential © 200X Abbott

SUMMARY - DOLF OBJ 3 + NEW PHASE

• Achieved 90% of the stated objective – Grant written, submitted and funded

– Base PK/PD completed

– Efficacy in jirds/rats to complete

• Second phase activities moving ahead rapidly – Reformulation has occurred

– Toxicology underway

– Efficacy studies arranged

• IND submitted by Jan 2013 (?)

VIEW

• We soon need to think about:

– How we move to human trials post a successful IND submission?

– How it would be used? Increasing the “menu” of tools for elimination and control programs, and for individual treatment

• A need for more Pharma partners – through a consortium?