Tyrosine Kinase Inhibitors pharmacology

PharmacologyPharmacology ofofTyrosine Kinase Tyrosine Kinase InhibitorsInhibitors

Alain Astier, Pharm D, Ph DProfessor in Clinical Pharmacy and Biotechnics

Vice-President ESOPDepartment of Pharmacy and Toxicology, CNRS-UMR 7054

Henri Mondor University Hospital, Creteil, France

A. A. AStierAStier ,,BavBavèènene, 28 juin 2008, 28 juin 2008

BackgroundBackground

MolecularMolecular targetedtargeted therapies (therapies (MTTsMTTs) are major ) are major advances in modern cancer careadvances in modern cancer care““NibsNibs”” are prototype of are prototype of MTTsMTTsTheir mechanisms of action are very different Their mechanisms of action are very different from classical from classical cytotoxiccytotoxic drugsdrugsMTTsMTTs come with broad range of unique side come with broad range of unique side effects different from classical effects different from classical cytotoxiccytotoxic agentsagentsMTTsMTTs are usually administered by oral route and are usually administered by oral route and for long time, mimicking classical treatments of for long time, mimicking classical treatments of chronic diseases chronic diseases


BackgroundBackground

Classical cancer treatment act by inhibition of cell Classical cancer treatment act by inhibition of cell proliferation at DNA level (DNA synthesis, DNA proliferation at DNA level (DNA synthesis, DNA duplication= duplication= cytotoxiccytotoxic drugs)drugs)

No specificity = strong toxicity upon normal proliferating No specificity = strong toxicity upon normal proliferating cells (gut, BMcells (gut, BM……))

MTT act by interactions with MTT act by interactions with Extra or intracellular signaling pathways (Extra or intracellular signaling pathways (TKIsTKIs))MicroMicro--environment: environment: vascularizationvascularization of tumor of tumor ((antiangiogenicantiangiogenic bevacizumabbevacizumab), ), metastasingmetastasing potentialpotential……More specific for some kind of cancer cells= no toxicity (or More specific for some kind of cancer cells= no toxicity (or modest) on normal proliferating cellsmodest) on normal proliferating cells


Normal Cell Communication

Proteins

mRNA

Genes

Some communications pathways

Cell autodestructs

Cell divides

Receptors

From NCI Understanding Cancer and Related TopicsUnderstanding Molecular Diagnostics


Cancer: A Communication Failure

Retinoblastoma, bone, bladder, lung, breast

Genes

Sarcomas

LeukemiaSome neuronal tumors

Colon Many cancers

Leukemia, brain,

breast, stomach,

lung

ProteinsmRNA

From NCI Understanding Cancer and Related TopicsUnderstanding Molecular Diagnostics

Target


Receptors with tyrosine Receptors with tyrosine kinasekinase activityactivity

HER2 HER3 HER4EGFR

TGF-α, ΑR,ΒΤC

EGF

NR NR, BTC, EPR, HB-

EGF

HER (erbB) family

VEGFR-2 VEGFR-3VEGFR-1

VEGF-A VEGF-B

VEGF-C VEGF-D

Flt-3

VEGFR family

PDGFR KIT

FL PDGF SCF

PDGFR family

PP

PP

VEGFRs, PDGFR, KIT, Flt-3

Mutant Flt-3

P

P

P

P

EGFR/HER2

PP

PP

Receptor Dimerization and Activation

VEGF-A VEGF-CVEGF-D

IGF-1R

P

P

P

P

IGF-1 IGF-2

FGFR1 FGFR2 FGFR3 FGFR4

FGFR family

A. A. AStierAStier ,,BavBavèènene, 28 juin 2008, 28 juin 2008 FromFrom Kuhn, NZW Kuhn, NZW congresscongress, , HamburgHamburg, 2008, 2008


A target : BCRA target : BCR--ABL proteinABL proteinFusion protein produced by Fusion protein produced by bcr/ablbcr/abl oncogeneoncogene issued from issued from chromosomicchromosomic translocation 9 translocation 9 -->22 in chronic myeloid leukemia>22 in chronic myeloid leukemia

Derivative chromosome 22 referred to as Philadelphia (Ph1) chromosome.

BCRBCR--ABL have strong tyrosine ABL have strong tyrosine kinasekinase activity and induce cell activity and induce cell proliferation (= proliferation (= oncogeneoncogene))

Target of some Target of some TKIsTKIs ((imatinibimatinib, , erlotiniberlotinib, , dasatinibdasatinib))

In BCR-ABLexpressing cells, imatinib produces three related effects: inhibition of BCR-ABL, autophosphorylation and substrate phosphorylation, inhibition of proliferation, and induction of apoptosis


CML or GIST tyrosine CML or GIST tyrosine kinasekinaseinhibitorsinhibitors

Drugs inhibit tyrosineDrugs inhibit tyrosine--kinasekinase activities at activities at intracellular levelsintracellular levels

Drug mustDrug mustpenetrate inside cellspenetrate inside cellsbe maintained continuously at an efficient be maintained continuously at an efficient

levellevel

What are the factors influencing What are the factors influencing TKIsTKIsactivity ?activity ?


BehaviorBehavior of of drugdrug insideinside the bodythe bodyPharmacokineticsPharmacokinetics PharmacodynamicsPharmacodynamics

[ ]

Absorption

Elimination

Métabolism

Distributioneffects

Transporters (ABC, OCT)

Concentration and residence time


MechanismMechanism of action for of action for imatininbimatininb

Competitive blockade at the site of fixation for ATP

Blockade is depending of the concentration and length of exposure of TKIs at the active site of BCR-ABL


Resistances to Resistances to imatinibimatinib


Elimination of drugs (Elimination of drugs (TKIsTKIs))Sum of metabolism and excretionSum of metabolism and excretion

Elimination of drugs can strongly depend on Elimination of drugs can strongly depend on individual patient characteristics:individual patient characteristics:

Heredity: enzymatic activities depending on Heredity: enzymatic activities depending on heredity (metabolism enzymes, transporters)heredity (metabolism enzymes, transporters)Acquired pathologies :renal or hepatic Acquired pathologies :renal or hepatic dysfunctionsdysfunctionsInteractions with food, drugs, alcohol, Interactions with food, drugs, alcohol, tobaccotobacco……

Variability in drug responses and/or drugVariability in drug responses and/or drug--related toxicitiesrelated toxicities


Consequences for treatmentsConsequences for treatments

It is not possible to modify hereditaryIt is not possible to modify hereditary--acquired acquired pharmacokinetic and pharmacokinetic and pharmacodynamicpharmacodynamic capacities but capacities but possible to identify patients possible to identify patients a prioria priori

It is possible and recommended to manage acquired It is possible and recommended to manage acquired elimination impairmentselimination impairments

It is It is mandatorymandatory to control behavioralto control behavioral--linked linked pharmacokinetics alterations i.e.pharmacokinetics alterations i.e.

Food interactionsFood interactionsDrug interactionsDrug interactionsComplianceComplianceHabits (smoking, drinkingHabits (smoking, drinking……))


Plasma concentrationPlasma concentration--effect effect relationshipsrelationships

FromFrom Kuhn, NZW Kuhn, NZW congresscongress, , HamburgHamburg, 2008, 2008


ConsequencesConsequencesIt is essential to obtain It is essential to obtain and maintain adequate and maintain adequate plasmatic levelsplasmatic levelsAvoid any cause lowering Avoid any cause lowering plasmatic levelsplasmatic levels

inefficacyinefficacyAvoid any cause Avoid any cause increasing plasmatic increasing plasmatic levels levels

toxicitytoxicityAvoid any cause inducing Avoid any cause inducing plasmatic levels variabilityplasmatic levels variability

Inefficacy

Toxicity

Ratio of toxic level to efficacy level

is the therapeutic index

inefficacy, toxicity, induction of inefficacy, toxicity, induction of resistanceresistance

http://www.biomedcentral.com/1472-6904/6/1/figure/F20?highres=y


Adherence to medication Adherence to medication Major problem with oral drugsMajor problem with oral drugsin chronic diseases:in chronic diseases:

AntiAnti--hypertensivehypertensiveLipids lowering Lipids lowering AntidiabeticAntidiabeticAntiretroviral ! Antiretroviral ! Anticancer !Anticancer !

Difference betweenDifference betweenExecution: irregularity of takingExecution: irregularity of takingPersistence: length of time during which the medication is takenPersistence: length of time during which the medication is taken


Incidence of nonIncidence of non--adherenceadherenceAntihypertensive drugsAntihypertensive drugs

3232--38 % 6 months (38 % 6 months (VrijensVrijens et al, BMJ, 2008et al, BMJ, 2008))4949--52 % 12 months (52 % 12 months (Bloom et al, BMJ, 2001Bloom et al, BMJ, 2001))

TamoxifenTamoxifen35 % at 3.5 years 35 % at 3.5 years

((Barron et al, Cancer, 2007Barron et al, Cancer, 2007))

GefitinibGefitinib (TKI)(TKI)1414--36 %36 %

((Lesley, Lung Cancer 2005Lesley, Lung Cancer 2005))

ImatinibImatinib28 % at 5 years28 % at 5 years

(IRIS trial)(IRIS trial)


ImatinibImatinib adherenceadherence

*Time on therapy without significant gaps in refills.

685

Patie

nts

Months0–1

35003000250020001500

0

1000500

1–2 2–3 3–4 4–5 5–6 6–7 7–8 8–9 9–1010–1111–1212–1313+

2921Patients taking recommended dose of

imatinib

In this US study of patients with either CML and GIST persistency* was near 100% at month 4 Persistency declined from 94% at month 5, to 23% at month 14

Tsang J-P, Rudychev I, Pescatore SL. J Clin Onc. 2006; 24:330s. Abstract 6119


NonNon--adherenceadherence

Adherence could strongly depend on the Adherence could strongly depend on the sideside--effects acting on the overall quality of effects acting on the overall quality of lifelife

Reducing Reducing evitable sideevitable side--effectseffects could could increase adherenceincrease adherence

Major role of Major role of patient education


MetabolismMetabolism

Phase I Phase II


Drug interactions Drug interactions Example of Example of NilotinibNilotinib

Competitive inhibitor of CYP3A, 2C8, 2C9, 2D6, Competitive inhibitor of CYP3A, 2C8, 2C9, 2D6, UGT1A1UGT1A1

Increasing concentration of Increasing concentration of midazolammidazolam 30 %30 %

Drug affecting Drug affecting nilotinibnilotinib metabolism metabolism KetoconazoleKetoconazole (400 mg 6 days) : inhibitor(400 mg 6 days) : inhibitor

AUC 300 %AUC 300 %

RifampicinRifampicin (600 mg 12 days) : activator(600 mg 12 days) : activatorAUC 80 %AUC 80 %

OverOver--exposure : serious effects, lifeexposure : serious effects, life--threatening threatening


A. A. AStierAStier ,,BavBavèènene, 28 juin 2008, 28 juin 2008 FromFrom Kuhn, NZW Kuhn, NZW congresscongress, , HamburgHamburg, 2008, 2008

Proton pump inhibitors (famotidine, omeprazole) decrease absorption of Dasatinib by 60 % (10 hr before) and anti-acids by 55 % (2 hr window)


Effects of food interactionEffects of food interactionAs compared to fasting:

ImatinibNo difference

Nilotinib 2 hrs PC (No food X 1 hr Post)Cmax ↑30% 2 hr post light meal;55% 30 min post light meal112% 30 min post high fatNot to be taken within 2hr after eatingWait 1 hr before any food

DasatinibNo difference

A. A. AStierAStier ,,BavBavèènene, 28 juin 2008, 28 juin 2008 Wilkinson GR, N Engl J Med 2005;352:2211-21.

PrePre--systemic interaction: grapefruitsystemic interaction: grapefruit

Same behavior with several other TKIs


Drug interactionsDrug interactionsPrescribed medications Prescribed medications

potentially important but not really a problempotentially important but not really a problem

SelfSelf--medication: medication: important problem, underestimatedimportant problem, underestimated

Alternative (herbal) medicines, OTC products Alternative (herbal) medicines, OTC products (e.g. vitamins, (e.g. vitamins, NSAIDsNSAIDs), nutritional supplements ), nutritional supplements and foodstuffsand foodstuffs (grapefruit(grapefruit……))

major problem, very underestimatedmajor problem, very underestimated


Effect of (bad) habitsEffect of (bad) habits

FromFrom Kuhn, NZW Kuhn, NZW congresscongress, , HamburgHamburg, 2008, 2008



ConclusionConclusion

TKIsTKIs are efficient new treatments for CML, GIST are efficient new treatments for CML, GIST and many other malignanciesand many other malignancies

Best efficacy will be only obtained if several Best efficacy will be only obtained if several major problem are managed:major problem are managed:

DrugDrug--related siderelated side--effectseffectsToxicity or inefficacy induced byToxicity or inefficacy induced by

Drugs interactionsDrugs interactionsFoods interactionsFoods interactions

Insufficient adherenceInsufficient adherence


Conclusion: Patient educationConclusion: Patient educationEssential forEssential for

Drug efficacyDrug efficacyControl of sideControl of side--effectseffects

Major role ofMajor role ofDoctorsDoctorsPharmacistsPharmacistsNursesNursesPatient advocatesPatient advocatesIndustry ?Industry ?

Respective roles could differ from country to countryRespective roles could differ from country to country

Multidisciplinary approach neededMultidisciplinary approach needed


ThankThank youyou !!

Documents

Tyrosine Kinase Inhibitors pharmacology