Luzelena Caro(1), Jongtae Lee(2), Ed Feng(1), Bei Yang(2), Sunny Chapel(2), Julie Stone(1), Larissa Wenning(1)
(1) Merck & Co., Inc., Kenilworth, NJ (2) Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan
Objectives: To use population PK modeling to characterize the effect of Japanese ethnicity on the non-linear plasma pharmacokinetics of grazoprevir, a component of the ZepatierTM combination approved HCV treatment, and to simulate the pharmacokinetics of various Japanese HCV patient subpopulations in order to predict PK/PD relationships in Japanese patients.
Methods: PK data in Japanese subjects obtained from one Phase 1 study and one Phase 2 and 3 study together with PK data in non-Japanese subjects from 7 Phase 1 and 12 Phase 2/3 studies were included in the population PK modeling. Japanese grazoprevir plasma concentrations were fitted to a pharmacokinetic model using non-linear mixed-effects modeling implemented in NONMEM V7 [1]. Empirical Bayes estimates of steady-state grazoprevir PK exposure (AUC0-24) for Japanese patients in the Phase 2 and 3 studies were used to assess exposure in various Japanese patient subpopulations.
Results: The Japanese non-linear and greater than dose-proportional grazoprevir PK profiles were well-characterized by the grazoprevir two-compartment population PK model with first-order elimination, two parallel first-order oral absorption pathways, and dose-dependent apparent clearance, apparent volume of distribution, and distribution rate constants. These results demonstrate that Japanese ethnicity is a significant covariate for apparent clearance but not for apparent volume of distribution or distribution rate constants. The final PK model allowed simulation of the once-daily administration of grazoprevir (when administered together with elbasvir, the other component of ZepatierTM) in Japanese HCV patients. The results demonstrate that steady-state grazoprevir AUC in Japanese HCV patients is estimated to be ~2-fold higher than that for non-Japanese HCV patients. The simulations also suggest that body weight, age, gender, and cirrhosis did not have a clinically relevant effect on grazoprevir steady-state AUC0-24, resulting in less than a 75% increase in grazoprevir exposure in Japanese HCV patients.
Conclusions: Modeling and simulation of grazoprevir pharmacokinetics in Japanese HCV Patients suggest that the higher exposure observed compared to non-Japanese patients is attributed to reduced apparent clearance. The exposure changes in Japanese subpopulations (e.g., elderly, female, low body weight) are not expected to be clinically relevant.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 25 () Abstr 6032 [www.page-meeting.org/?abstract=6032]
Poster: Drug/Disease modeling - Other topics