Population PK/PD Modeling of a Hepatitis C NS3 Inhibitor
M. Ruppert (1), K. Bol (1), R. Hooijmaijers (2), E. Olek (3), N. Treijtel (1), E. Spaans (1).
(1) Kinesis Pharma, Breda, the Netherlands; (2) Employed at Kinesis Pharma at the time of investigation; (3) Achillion Pharmaceuticals, Inc, New Haven, USA.
Objectives: ACH-0141625, currently in development for treatment of HCV infection, is a potent inhibitor of HCV NS3 protease suited for once daily oral dosing. The aim of this modeling exercise is to evaluate several candidate dosing regimens on their impact on PK and viral load.
Methods: A pharmacokinetic model was built in NONMEM v6 using data from a randomized, double-blind, placebo controlled dose escalating phase 1 study on both healthy volunteers and hepatitis C infected subjects. Absorption was described with a time-dependent first order absorption rate. An increase in bioavailability for subsequent intakes was implemented, as well as a food effect. Subsequently, individual PK curves were linked to anti-viral activity using a viral dynamics model as described by Neumann et al.[1] Due to a prolonged anti-viral effect after the end of treatment, efficacy was related to concentrations in an effect compartment. Simulations were performed to assist in choosing a next dosing level, to evaluate the necessity of a loading dose and to assess the anti-viral effect for several different dosing schemes.
Results: A VPC confirmed that the PK model described the data well. Bioavailability for multiple dosing increased 3-fold for fasted intakes and 6-fold for fed intakes. Simulations showed that a loading dose can be used for reaching near steady state after one intake, but that the effect on viral inhibition is negligible. Estimates for EC50 and EC90 were obtained by linking anti-viral efficacy to individual PK curves. The effect-site equilibrium delay rate constant implied that steady state at the site of action will be reached in about 3 days. Simulation showed that all patients receiving 200 mg QD fed, 200 mg QD fed with an accidental fasted intake at steady state or 200 mg QD fasted would reach trough concentrations at the site of action above the EC50. Corresponding fractions of patients reaching trough concentrations above EC90 are 100%, 99.8% and 98.4%, respectively.
Conclusion: Viral load was described well using a viral dynamics model as described by Neumann but with the effect linked to an effect compartment. As fluctuations in concentration at the site of action are small, it shows that average plasma concentrations are more relevant than plasma C0h.
References:
[1] Neumann, A.U., Lam, N.P., Dahari, H, Gretch, D.R., Wiley, T.E., Layden, T.J., Perelson, A.S. - Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon-α Therapy. Science 1998/10; Vol. 282 no. 5386 pp. 103-107
