Population pharmacokinetics and exposure–response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma
Tóm tắt
To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma. Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C
min) or average concentration] on response rates and progression-free survival (PFS) was examined. Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed C
min above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL). No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL.
Tài liệu tham khảo
Korn EL, Liu PY, Lee SJ et al (2008) Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 26:527–534
Gillmartin AG, Bleam MR, Groy A et al (2011) GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 17:989–1000
Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:948–954
Infante J, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VGR, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA III, Messersmith WA (2012) Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 13:773–781
Leonowens C, Pendry C, Bauman J, Young GC, Ho M, Henriquez F, Fang L, Morrison RA, Orford K, Ouellet D (2014) Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours. Br J Clin Pharmacol 78(3):524–532
Cox DS, Papdopoulos K, Fang L, Bauman J, LoRusso P, Tolcher A, Patnaik A, Pnedry C, Orford K, Ouellet D (2013) Evaluation of the effects of food on the single-dose pharmacokinetics of trametinib a first-in-class MEK inhibitor, in patients with cancer. J Clin Pharmacol. doi:10.1002/jcph.115
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD (2013) Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clinical Oncol 31(4):482–489
Flaherty KT, Robert C, Hersey P, Nathan P et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367(2):107–114
Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT, Peddareddigari VJR, Lebowitz PF, Le NT, Burris HA III, Messersmith WA, O’Dwyer PJ, Kim KB, Flaherty K, Bendell JC, Gonzalez R, Kurzrock R, Fecher LA (2012) Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 13:782–789
Ho MYK, Morris MJ, Pirhalla JL, Bauman JW, Pendry CB, Orford KW, Morrison RA, Cox DS (2014) Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers. Xenobiotica. doi:10.3109/00498254.2013.831143
Beal S, Sheiner LB, Boeckmann A (2011) NONMEM user’s guides. Icon Development Solutions Ellicott City, Maryland
Harrell FE (2001) Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. Springer, New York
Wahlby U, Jonsson EN, Karlsson MO (2001) Assessment of actual significance levels for covariate effects in NONMEM. J Pharmacokinet Pharmacodyn 28(3):231–252
Wahlby U, Bouw MR, Jonsson EN, Karlsson MO (2002) Assessment of type I error rates for the statistical sub-model in NONMEM. J Pharmacokinet Pharmacodyn 29(3):251–269
Yano Y, Beal SL, Sheiner LB (2001) Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 28:171–192
Bergstrand M, Hooker AC, Allini JE, Karlsson MO (2011) Prediction corrected visual predictive checks for diagnosing nonlinear mixed effects models. AAPS J 13(2):143–151
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guidelines (version 1.1). Eur J Cancer 45:228–247
Flaherty KT, Hennig M, Lee S, Ascierto PA et al (2014) Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials. Lancet Oncol. doi:10.1016/S1470-2045(14)70007-5
Chiu J, Ouellet D. Exposure-response analysis of the effect of trametinib, a MEK inhibitor, on tumor size in patients with V600 BRAF mutation positive melanoma. In: American conference on pharmacometrics (ACoP) meeting 2013; abstract W-017, Fort Lauderdale