Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors · Therapeutic Drug Monitoring of...

Therapeutic Drug

Monitoring of Tyrosine

Kinase Inhibitors

Nicolas Widmer, PharmD, PhD

Division of Clinical Pharmacology

Centre Hospitalier Universitaire Vaudois

and University of Lausanne

Switzerland

Drug Monitoring Symposium

Swiss MedLab 2012

Plan

• Introduction

• TKI concentration measurement

• TKI pharmacokinetics

• TKI concentration-effect relationship

• Levels of evidence of TKI TDM

• How to perform TKI TDM?

• Conclusion

Introduction

• Protein kinases

– 518 human PK

– Among which 90 tyrosine kinases (TK)

– Responsible for the activation of signal transduction cascades (through phosphorylation processes)

Manning G, Whyte DB, et al. Science 2002

Introduction

• Tyrosine kinase inhibitors (TKI)

– Drugs that

inhibit tyrosine

kinases

– Mainly used as

anticancer drugs

– 13 TKIs approved

by FDA

– Tenth of TKIs are presently in development

Savage DG, Antman KH. N Engl J Med 2002

Introduction TKI Year of FDA approval Target Indication

Imatinib

(Gleevec®, Glivec®) 2001 BCR-ABL, c-KIT, PDGRF

CML, ALL

GIST

Gefitinib

(Iressa®) 2003 EGFR NSCLC

Erlotinib

(Tarceva®) 2004 EGFR

NSCLC

Pancreatic cancer

Sorafenib

(Nexavar®) 2005

VEGFR, PDGRF, RAF,

Mek, Erk

HCC

RCC

Sunitinib

(Sutent®) 2006

FLT3, PDGFR, VEGFR,

KIT

RCC, GIST

Pancreatic NET

Dasatinib

(Sprycel®) 2006 Src, ABL CML, ALL

Lapatinib

(Tyverb®) 2007 EGFR, HER2 HER2+ BC

Nilotinib

(Tasigna®) 2007 BCR, ABL CML

Pazopanib

(Votrient®) 2009 VEGFR RCC

Vandetanib

(Caprelsa®) 2011 VEGFR, EGFR Thyroid cancer

Crizotinib

(Xalkori®) 2011 ALK, HGFR; cMet ALK+ NSCLC

Ruxolitinib

(Jakafi®) 2011 JAK Myelofibrosis

Axitinib

(Inlyta®) 2012 VEGFR, PDGFR, c-KIT RCC

Introduction

• The example of imatinib

– First targeted anticancer drug for the treatment of:

• Chronic myeloid leukemia (CML)

• Gastrointestinal stromal tumors (GIST)

– Designed to inhibit the PDGF receptor and the

BCR-ABL tyrosine kinase (hallmark of CML)

– Also found to inhibit the tyrosine kinase receptor

c-KIT (involved in the pathogenesis of GIST)

Introduction

• TKI drawbacks – They must be taken indefinitely

– Resistance occurs in a significant number of patients

– They are not devoid of toxicity (e.g. cutaneous, cardio-vascular)

– They are substrate of CYP (mainly 3A4) and P-gp/hOCT1 and bound to plasma proteins => High PK variability and susceptible of drug or food interactions

– Such new therapies remain fairly expensive

– Important compliance issue is observed

Introduction

• Are TKIs candidates for a TDM

approach ?

• Main criteria for TDM

– Availability of an analytical technique

– High inter-individual PK variability

and low intra-individual PK variability

– PK-PD relationships

– Prospective randomized clinical trials

Widmer N, Csajka C, et al. Rev Med Suisse 2008

TKI measurement

• HPLC-UV

– Various methods published (useful for district hospitals)

• LC-MS/MS

– Reference method (e.g. EUTOS)

– High cost (still reserved to university hospitals)

• Immunoassay

– Under development

Haouala A, Zanolari B, et al. J Chrom B 2009

Widmer N, Beguin A, et al. J Chrom B 2004

http://www.saladax.com/

TKI pharmacokinetics

Drug

Alb/AGP

Free / bound

Binding

Liver

Metabolism

CYP3A4

Blood

GI tract

Target cell

Extracellular / intracellular

Efflux

Influx

OCT1

P-gp

Metabolism

Efflux

P-gp

CYP3A4

Metabolism modulation (CYP)

Circulating protein amount variability

Modification of the cellular disposition

Variability in the sensitivity of the target (mutation, etc.)

Decosterd LA, Widmer N. Division of Clinical Pharmacology UNIL-CHUV


Klümpen HJ, Samer CF, et al. Cancer Treat Rev 2011 See also: Di Gion P, Kanefendt F, et al. Clin Pharmacokin 2011

Scheffler M, Di Gion, P, et al. Clin Pharmacokin 2011


Klümpen HJ, Samer CF, et al. Cancer Treat Rev 2011

TKI PK variability

• Exemple of imatinib in adults

6-fold

Widmer N, Decosterd LA, et al. Br J Clin Pharmacol 2006 Time since last 400 mg-drug intake [h]

Imat

inib

pla

sma

con

cen

trat

ion

(ad

just

ed)

[µ

g/L

]

Parameter Population

mean Inter-individual

variability

ka (h-1) 0.61

Vd (L) 347 63%

CL (L/h) 14.2 36%

BW 12.7

SEX 0.0

AGE -2.2

PATHO -1.0

(CV%) 31%

Data of CML and GIST patients

TKI PK variability

• Exemple of imatinib in adults

Demetri GD, Wang Y, et al. J Clin Oncol 2009 Larson RA, Druker BJ, et al. Blood 2008

IRIS study: CML patients B2222 study: GIST patients

TKI PK variability

• Exemple of erlotinib (PK meta-analysis)

Petit-Jean E, Decosterd LA, et al [in preparation]

4447

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0 5 10 15 20 25 30

Reference percentiles curves

for an administration 150 mg QD IC5

IC10

IC25

IC50

IC75

IC90

IC95

Cmax (ng/mL)

Cmin ng/mL

IC50 cal

IC50 mouse

Ctumor

P10

P5

P25

P50

P10 P75

P90

P95

IC50

TKI PK variability


TKI PK-PD relationships

• Imatinib PK relationships with efficacy

Picard S, Titier K, et al. Blood 2007 ROC curve analysis: Cmin cutoff = 1002 ng/ml

CML patients



Q1

Q4

Q2-3

Larson RA, Druker BJ, et al. Blood 2008 Cmin in CCyR-patients: 1009 ± 544 ng/ml

Q1 Q2-3 Q4

Conc. [µg/L] 490 ± 120 889 ± 148 1661 ± 602

RESPONSE

CCyR 5 yr

MMR 2 yr

75.9 %

63 %

85.4 %

78 %

91.9 %

86 %

DISCONTINUATION

- efficacy issues

- AE

41.4 %

18.4 %

4.6 %

27.5 %

15.2 %

2.8 %

23.3 %

8.1 %

7 %

CML patients



Demetri GD, Wang Y, et al. J Clin Oncol 2009 => Patients with Cmin > 1100 ng/ml (> Q1) had higher rates of objective response

GIST patients



– However, contradictory results exist:

• Canadian study: no PK-PD correlations observed

• UK study: Cmin > 0.95 µM (560 ng/ml) could be

sufficient to reduce the incidence of resistance

(i.e. lack of HR after 3 mo or of CCyR after 6 mo)

Forrest DL, Trainor S, et al. Leuk Res 2009

Singh N, Kumar L, et al. Eur J Clin Pharmacol 2009; Li-Wan-Po A, Farndon P, et al. Eur J Clin Pharmacol 2010

CML patients


• Sunitinib PK relationships with efficacy

Houk BE, Bello CL, et al. Cancer Chemother Pharmacol 2005


• Imatinib PK relationships with toxicity

Delbaldo C, Chatelut E, et al. Clin Cancer Res 2006

The best observed correlation corresponded to the percentage of “absolute neutrophile count” versus imatinib AUCu on day 30 (p < 0.001)

Warning: extrapolated free

concentrations (i.e. not measured !)

GIST patients


• Imatinib PK relationships with toxicity

Widmer N, Decosterd LA, et al. Br J Cancer 2008

OR 2.9 ± 0.6 for a 2-fold free AUC increase; p < 0.001

Total and free AUC correlated with the number of side effects (CML and GIST patients)


• Erlotinib PK relationships with toxicity

Lu JF, Eppler SM, et al. Clin Pharmacol Ther 2006

Level of evidence for TKI TDM

• Main criteria for TDM

– Availability of an analytical technique

– High inter-individual PK variability

and low intra-individual PK variability

– PK-PD relationships

– Prospective randomized clinical trials

Buclin T, Widmer N, et al. Lancet Oncol 2011 Teng JFT, Mabasa VH, et al. Ther Drug Monit 2012

How to perform TKI TDM?

• Trough level

– Target: > 1000 ng/ml in CML patients

> 1100 ng/ml in GIST patients

1

Improvement of TDM of imatinib

by Bayesian prediction of

trough levels

V Gotta1, N Widmer1, M Montemurro2, S Leyvraz2, A Houala1, LA Decosterd1,

C Csajka1, T Buclin1

1Division of Clinical Pharmacology & 2Multidisciplinary Oncology Center

Centre Hospitalier Universitaire Vaudois (CHUV) and

University of Lausanne, Lausanne, Switzerland

CL

Dose

Introduction: imatinib

Chronic myeloid leukemia (CML)

Pharmacokinetics (PK) Main Indications

Widmer N et al. Br J Clin Pharmacol 2006; Schmidli H et al. Br J Clin Pharmacol 2005; Petain A et al. Clin Cancer Res 2008; Menon-Andersen D et al. Cancer Chemother Pharmacol 2009

1-compartment model:

Gastrointestinalstromal tumors (GIST)Vd

Introduction: imatinib

PK variability

CL & V↑

CVCmin 40-60% inter-patient variability

CVCmin 20-30% intra-patient variability

τ

Gotta V & Molimard M et al., unpublished Data (EUTOS project)Peng et al. J Clin Oncol 2004; Widmer N et al. Br J Clin Pharmacol 2006…

Introduction: imatinib TDM

Cmin ~ optimal response

PK – PD relationships

Larson RA et al. Blood 2008Demetri GD et al. J Clin Oncol 2009Widmer et al. Br J Cancer 2008

CML: Optimal molecular

Response

78-86% (Q2-Q4)

63%

(Q1 or < 650ng/ml)

GIST: Time to progression

30 months (Q2-Q4)

11.3 months

(Q1 or < 1100ng/ml)

τ

AUC ~ toxicity signs

Introduction: imatinib TDM

Problems for performing TDM

Cobs ≠ Cmin

τ

???

Cobs

Objectives

Sheiner LB et al. Clin Pharmacol Ther 1979;Rodman JH et al. Applied PK & PD – Principles of TDM. 4th ed. Lippincott Williams & Wilkins; 2006

τ

« Given Cobs , what are the maximum a posteriori (MAP)

individual values of CL and V ? »

Cmin

(1) uncorrelated

ρCL,V

V

(2) correlated

CL

Gotta V, Molimard M, et al. Bordeaux imatinib BLT database NONMEM analysis

4095 plasma imatinib samples observed from 2478 CML patients obtained in the scope of routine therapeutic drug monitoring in Europe


• Percentile curves for random samples

Von Mehren M, Widmer N. Cancer Treat Rev 2011

Imatinib percentile curves in a GIST patients population

Patient

Patient


• Published whole PK curves

Lapatinib in metastatic cancers

Patient

Buris III HA, Hurwitz HI, et al. J Clin Oncol 2005


• Bayesian prediction of trough level

Gotta V, Widmer N, et al. Clin Pharmacokin 2012

Conclusions

– Level of proof for

TDM of imatinib varies

between « potentially

useful » and

« recommended »

– For other TKI it varies

between « remaining

to evaluate » and

« potentially useful »

Le Guellec C, Simon N, et al. La Lettre du Pharmacologue 2009 Bouchet S, Boyer B, et al. Therapie 2010

Conclusions

• Results from randomized prospective

clinical trials are warranted !

http://www.imatinib-monitoring.ch/ Verena G, Buclin T, et al. Division of Clinical Pharmacology and Toxicology UNIL-CHUV

I-COME trial

http://www.imatinib-monitoring.ch/



Perspectives

• Establishing cut-off concentrations

(efficacy/toxicity) => therapeutic interval

• Measuring free concentrations

• Extrapolating accurate free concentrations

• Integrating PG and target genetics

• Considering situation in children

• Evaluating intracellular PK/PD relationship

Haouala A, Widmer N, et al [submitted]

Streit F, Binder L, et al. Ther Drug Monit 2011

Li-Wan-Po A, Farndon P, et al. Eur J Clin Pharmacol 2010; Takahashi N, Miura M. Pharmacology 2011

Petain A, Kattygnarath D, et al. Clin Cancer Res 2008; Menon-Andersen D, Mondick JT, et al. Cancer Chemother Pharmacol 2009

Decosterd LA, Buclin T. FNRS grant 2011

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