Population Pharmacokinetic Modeling of Simeprevir – Odalasvir Interaction in Healthy Volunteers
E. Valade (1), E. Hoeben (1), T.N. Kakuda (2), M. McClure (2), C. Westland (2), J. Perez Ruixo (1) and O. Ackaert (1)
(1) Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B 2340 Beerse, Belgium; (2) Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, CA, USA.
Objectives: To develop a joint population (pop) pharmacokinetic (PK) model describing the PK interaction between simeprevir (SMV) and odalasvir (ODV), two direct-acting antiviral agents (DAAs) for the treatment of patients with chronic hepatitis C (CHC) infection.
Methods: The data used in the analysis were obtained from a phase 1, open-label, two group, fixed-sequence study in healthy volunteers (HV) [1]. A total of 997 SMV (344 in monotherapy, 653 in combination with ODV) and 1215 ODV (403 in monotherapy, 812 in combination with SMV) plasma concentrations were used. The data were analyzed by a non-linear mixed effects modelling approach, using NONMEM software [2]. Previous models describing the PK of SMV [3] and ODV (data on file) in monotherapy were used to quantify the PK of SMV and ODV in the absence of interaction. Based on available information, the effect of SMV on ODV apparent clearance (CL/F) and relative bioavailability was evaluated. Similarly, the effect of ODV on SMV mean transit time, relative bioavailability (Frel), and the parameters quantifying the SMV Michaelis-Menten elimination (Vmax and Km) was investigated. The effect of a compound on the other one was tested as a categorical covariate or as being dependent on the other compound’s predicted concentration at each time point, according to different mechanism of PK interaction (i.e. competitive or non-competitive inhibition).
Results: The effect of SMV on ODV was best described by an inhibition of CL/F with an Imax model depending on SMV predicted concentrations. Imax and IC50 were estimated to 46.7% and 257 ng/mL, respectively. The effect of ODV on SMV was best described by a combination of a categorical effect on SMV Frel and a competitive inhibition on SMV elimination. In presence of ODV, SMV Frel increased by 26% whereas SMV Km doubled at ODV concentrations of 1610 ng/mL.
Conclusions: A popPK model describing the dual ODV-SMV PK interaction has been developed in HV and was able to capture the increase of SMV and ODV exposures when administered together. This model can be used to investigate the impact of these PK interactions in patients with CHC infection receiving different dosing regimens of ODV and SMV in combination with other DAAs.
References:
[1] https://clinicaltrials.gov/ct2/show/NCT02512562.
[2] NONMEM Users Guides (1989–2009). Beal SL, Sheiner LB, Boeckmann AJ, and Bauer RJ (eds). Icon Development Solutions, Ellicott City, MD.
[3] Viberg A, Petersson K, Hoeben E, Brochot A. A population PK model for simeprevir in healthy volunteers and patients. PAGE meeting; 2016; Lisboa, Portugal. Available from: http://www.page-meeting.org/?abstract=3368.
