Hechuan Wang (2), Liang Li (2), Yupeng Ren (2), Yue Qiu (2), Jenny Zheng (3), Gailing Li (3), Chuanpu Hu (4), Tianyan Zhou (1,2), Wei Lu (1,2)
(1) State of Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical; (2) Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, China; (3) Clinical Pharmacology, Janssen China R&D and Scientific Affairs, China; (4) Model Based Drug Development, Janssen R&D, USA
Objectives: To develop an integrated pharmacokinetic/viral kinetic (PK/VK) model to predict long-term virological response rates of daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV).
Methods: A systematic publication search was conducted for DCV or ASV monotherapy or combination therapy in healthy volunteers or patients infected with GT1 HCV. A total of 635 study-level aggregate concentrations from 10 trials were used to build PK models for DCV and ASV separately. An integrated PK/VK model[1] was sequentially developed to characterize the effect of DCV and ASV on HCV viral RNA load based on 952 individual-level data from 72 patients in 4 single or multiple ascending dose studies. Sigmoid Emax functions were applied to describe the antiviral effect of DCV and ASV, respectively, depending on the drug concentrations at the effect compartment. The combined efficacy of DCV and ASV was based on the Loewe additivity theory[2]. The PK/VK model was evaluated externally by comparing predicted virological response rates with observations.
Results: The developed PK/VK model could adequately describe both DCV and ASV PK profiles and viral load curves. The differences of IC50 in fold for GT1B vs. GT1A were fixed to the values (0.18 for DCV and 0.3 for ASV) reported in the previous pre-clinical studies[3,4]. IC50 of DCV was estimated to be 0.0306 μg/L (41.4 pM, RSE 55%) and 0.0055 μg/L (7.5 pM) for GT 1A and 1B replicons, respectively, indicating DCV has a great potency against both the GT 1A and 1B HCV replicons. IC50 of ASV in our model was estimated to be 2.28 μg/L (3 nM, RSE 82%) and 0.685 μg/L (0.91 nM) for GT 1A and 1B replicons, respectively. The coefficients of exponential function describing IC50 of DCV changing over time for GT 1A and 1B replicons were estimated to be 0.432 and 0.13, respectively. This result revealed IC50 of DCV would increase up to 423.3 and 6.2 fold for GT 1A and 1B replicons after 2 weeks monotherapy of DCV. The predicted virological response rates during- and post-treatment of combination therapy of DCV and ASV in HCV GT 1 patients are in general agreement with observed values in the external phase 3 clinical trial.
Conclusion: The proposed PK/VK model provides a useful platform for characterization of PK/PD relationships and predictions of long-term virological response rates to aid in future development of direct acting antiviral drugs.
[1] Snoeck E, Chanu P, Lavielle M, Jacqmin P, Jonsson EN, Jorga K, et al. A comprehensive hepatitis C viral kinetic model explaining cure. Clinical pharmacology and therapeutics 2010, 87(6): 706 – 713. [2] Koizumi Y, Iwami S. Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs. Theoretical biology & medical modelling 2014, 11: 41. [3] Scola PM, Sun LQ, Wang AX, Chen J, Sin N, Venables BL, et al. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. Journal of medicinal chemistry. 2014;57(5):1730-52. [4] Lee C. Daclatasvir: potential role in hepatitis C. Drug design, development and therapy. 2013;7(1223-33).
Reference: PAGE 24 () Abstr 3494 [www.page-meeting.org/?abstract=3494]
Poster: Drug/Disease modeling - Infection