Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors

Transcription

1 Drug Monitoring Symposium Swiss MedLab 2012 Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors Nicolas Widmer, PharmD, PhD Division of Clinical Pharmacology Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland

2 Plan Introduction TKI concentration measurement TKI pharmacokinetics TKI concentration-effect relationship Levels of evidence of TKI TDM How to perform TKI TDM? Conclusion

3 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

4 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

5 Introduction TKI Year of FDA approval Target Indication Imatinib (Gleevec, Glivec ) Gefitinib (Iressa ) Erlotinib (Tarceva ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Dasatinib (Sprycel ) Lapatinib (Tyverb ) Nilotinib (Tasigna ) Pazopanib (Votrient ) Vandetanib (Caprelsa ) Crizotinib (Xalkori ) Ruxolitinib (Jakafi ) Axitinib (Inlyta ) 2001 BCR-ABL, c-kit, PDGRF CML, ALL GIST 2003 EGFR NSCLC 2004 EGFR VEGFR, PDGRF, RAF, Mek, Erk FLT3, PDGFR, VEGFR, KIT NSCLC Pancreatic cancer HCC RCC RCC, GIST Pancreatic NET 2006 Src, ABL CML, ALL 2007 EGFR, HER2 HER2+ BC 2007 BCR, ABL CML 2009 VEGFR RCC 2011 VEGFR, EGFR Thyroid cancer 2011 ALK, HGFR; cmet ALK+ NSCLC 2011 JAK Myelofibrosis 2012 VEGFR, PDGFR, c-kit RCC

6 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)

7 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

8 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

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

10 TKI pharmacokinetics Drug Circulating protein amount variability GI tract P-gp Efflux Metabolism Blood Modification of the cellular disposition Variability in the sensitivity of the target (mutation, etc.) Metabolism modulation (CYP) Liver CYP3A4 Alb/AGP P-gp Efflux Target cell Metabolism Binding CYP3A4 Free / bound OCT1 Influx Extracellular / intracellular Decosterd LA, Widmer N. Division of Clinical Pharmacology UNIL-CHUV

11 TKI pharmacokinetics 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

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

13 Imatinib plasma concentration (adjusted) [µg/l] TKI PK variability Exemple of imatinib in adults 6-fold Parameter Population mean Inter-individual variability k a (h -1 ) 0.61 Vd (L) % CL (L/h) % BW 12.7 SEX 0.0 AGE -2.2 PATHO -1.0 (CV%) 31% Data of CML and GIST patients Time since last 400 mg-drug intake [h] Widmer N, Decosterd LA, et al. Br J Clin Pharmacol 2006

14 TKI PK variability Exemple of imatinib in adults IRIS study: CML patients Larson RA, Druker BJ, et al. Blood 2008 B2222 study: GIST patients Demetri GD, Wang Y, et al. J Clin Oncol 2009

15 TKI PK variability Exemple of erlotinib (PK meta-analysis) 5000 Reference percentiles curves for an administration 150 mg QD IC5 P5 IC10 P IC25 P25 IC50 P50 IC75 P10 P75 IC90 P90 IC95 P95 Cmax (ng/ml) Cmin ng/ml IC50 cal IC50 mouse Ctumor Petit-Jean E, Decosterd LA, et al [in preparation]

16 TKI PK variability Klümpen HJ, Samer CF, et al. Cancer Treat Rev 2011

17 TKI PK-PD relationships Imatinib PK relationships with efficacy CML patients ROC curve analysis: C min cutoff = 1002 ng/ml Picard S, Titier K, et al. Blood 2007

18 TKI PK-PD relationships Imatinib PK relationships with efficacy Q4 Q1 Q2-3 CML patients Q1 Q2-3 Q4 Conc. [µg/l] 490 ± ± ± 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 % C min in CCyR-patients: 1009 ± 544 ng/ml Larson RA, Druker BJ, et al. Blood 2008

19 TKI PK-PD relationships Imatinib PK relationships with efficacy GIST patients => Patients with C min > 1100 ng/ml (> Q1) had higher rates of objective response Demetri GD, Wang Y, et al. J Clin Oncol 2009

20 TKI PK-PD relationships Imatinib PK relationships with efficacy However, contradictory results exist: Canadian study: no PK-PD correlations observed Forrest DL, Trainor S, et al. Leuk Res 2009 UK study: C min > 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) 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

21 TKI PK-PD relationships Sunitinib PK relationships with efficacy Houk BE, Bello CL, et al. Cancer Chemother Pharmacol 2005

22 TKI PK-PD relationships Imatinib PK relationships with toxicity GIST patients Warning: extrapolated free concentrations (i.e. not measured!) The best observed correlation corresponded to the percentage of absolute neutrophile count versus imatinib AUC u on day 30 (p < 0.001) Delbaldo C, Chatelut E, et al. Clin Cancer Res 2006

23 TKI PK-PD relationships Imatinib PK relationships with toxicity Total and free AUC correlated with the number of side effects (CML and GIST patients) OR 2.9 ± 0.6 for a 2-fold free AUC increase; p < Widmer N, Decosterd LA, et al. Br J Cancer 2008

24 TKI PK-PD relationships Erlotinib PK relationships with toxicity Lu JF, Eppler SM, et al. Clin Pharmacol Ther 2006

25 TKI PK-PD relationships Klümpen HJ, Samer CF, et al. Cancer Treat Rev 2011

26 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

27 How to perform imatinib TKI TDM? Introduction: Trough level Target: PK variability > 1000 ng/ml in CML patients > 1100 ng/ml in GIST CL &patients V CVCmin 40-60% inter-patient variability CVCmin 20-30% intra-patient variability 4095 plasma imatinib samples observed from 2478 CML patients obtained in the scope of routine therapeutic drug monitoring in Europe τ Gotta V, Molimard M, et al. Bordeaux imatinib BLT database NONMEM analysis 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

28 How to perform TKI TDM? Percentile curves for random samples Patient Patient Imatinib percentile curves in a GIST patients population Von Mehren M, Widmer N. Cancer Treat Rev 2011

29 How to perform TKI TDM? Published whole PK curves Patient Lapatinib in metastatic cancers Buris III HA, Hurwitz HI, et al. J Clin Oncol 2005

30 How to perform TKI TDM? Bayesian prediction of trough level Gotta V, Widmer N, et al. Clin Pharmacokin 2012

31 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

32 Conclusions Results from randomized prospective clinical trials are warranted! I-COME trial Verena G, Buclin T, et al. Division of Clinical Pharmacology and Toxicology UNIL-CHUV

33 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 Streit F, Binder L, et al. Ther Drug Monit 2011 Haouala A, Widmer N, et al [submitted] 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 Evaluating intracellular PK/PD relationship Decosterd LA, Buclin T. FNRS grant 2011