A Population PK Model for Simeprevir in Healthy Volunteers and Patients
Anders Viberg(1), Klas Petersson(1), Eef Hoeben(2) and Anne Brochot(2)
(1) qPharmetra LLC, Huddinge, Sweden, (2) Janssen Research & Development LLC, Beerse, Belgium
Objectives: Simeprevir (SMV) is a once-daily second-generation hepatitis C virus (HCV) NS3/4A protease inhibitor. Here we present a population PK (popPK) model describing the temporal course of SMV concentration and use it to investigate the relationship between pharmacokinetics (PK) and a selection of baseline demographics and disease characteristics.
Methods: PK data from 2183 non-Asian and Asian healthy volunteers and HCV-infected patients from 15 different SMV studies (doses of 25-200 mg) were used for the development of a popPK model in NONMEM® [1]. Data from 14 studies were used when developing the model and quantifying the inter-individual and inter-occasion variability (IIV and IOV). The linearized covariate search described by Khandelwal et al. [2] was used when testing potential covariate relationships. Following inclusion of covariates, the model was used to predict the SMV PK in the last study where genotype 4-infected patients were studied.
Results: The PK of SMV was described by a two-compartment model with non-linear elimination and 3 transit compartments for absorption. The model chosen as the final covariate model included the impact of METAVIR score on relative bioavailability (Frel) and peripheral volume of distribution (V2), gender, Asian origin and ALT on Frel, age on maximum elimination capacity and mean transit time for absorption. The impacts of these covariates on exposure were all minor in relation to the large IIV. The model was able to accurately describe PK in the genotype 4-infected patients not included in the model development. AUC0-24h (median [5th to 95th percentile]) at steady-state following 150 mg once-daily dosing of SMV in non-Asian patients (n=1225) was estimated to be 46900 µg h/L (10900-285000), while C0h was estimated to be 1030 µg /L (149-9500).
Conclusions: The time course of SMV PK was described by a two-compartment model with Michaelis-Menten elimination and transit compartments for absorption. The variability in SMV exposure was large and the model suggests that the majority of this variability is associated with V2 where IIV was estimated to be 188%. The largest covariate effect was found for Asian patients with Frel predicted to be 70.4% higher as compared with non-Asian patients. However, the covariate effects on exposures were very small compared with the overall variability, indicating that the clinical relevance of the effect of Asian origin, METAVIR score, gender, age and ALT on SMV exposure is limited.
References:
[1] NONMEM 7.2 ICON Development Solutions, Elliot City, MD, USA.
[2] AAPS J. 2011 Sep;13(3):464-72.
