Annabelle Lemenuel-Diot, Micha Levi, Nancy Shulman and Nicolas Frey
F. Hoffmann La Roche
Objectives: DNV is an inhibitor of the HCV NS3/4A protease that has potent activity against HCV, and is currently in Phase 2 development for the treatment of Chronic Hepatitis C. The goal of this analysis was to describe the effect of DNV ± Ritonavir (RTV), which is used to enhance DNV exposures, and ± PEG-IFN/Ribavirin (P/R) on HCV RNA viral loads using a mechanistic viral kinetic (VK) model addressing the host-virus-drug interactions with system and drug effect parameters. The structure of the VK model was previously characterized on a large viral load database of CHC patients treated with P/R [1].
Methods: The effect of DNV has been incorporated in the VK model using available PK and viral load data from treatment-naive, non-cirrhotic patients with HCV genotype 1 infection in phase 1 and 2 clinical studies and was externally validated using another phase 1 study. The system and PEG-IFN effect parameters estimated in the previous model [1] were re-estimated to take advantage of the rich early viral kinetic information from the phase 1 studies. DNV treatment effect was investigated by including an exposure-dependent inhibition and/or induction on various model parameters, estimating parameters using MONOLIX [2].
Results: Re-estimating the free virion clearance, virion production rate, and PEG-IFN effect allowed a better description of the rapid early viral load decline. Free virion clearance was higher compared to previous estimates, in agreement with literature reports [3]. Two MoA were identified: inhibition of virion production and increase of the infected hepatocytes clearance. Good agreement was demonstrated between the observed and predicted time courses of response rate in phase 2 and viral load in phase 1.
Conclusions: A mechanistic VK model was developed to describe the effect of DNV ± RTV, and ± P/R on HCV viral load. Phase 1 data contributed to a better estimation of parameters related to the early viral decline. The additional effect on clearance of infected cells in addition to the inhibition of virion production is in agreement with earlier reports [4,5] suggesting that protease inhibitors have dual MoA; Inhibiting the virion production and restoring the immune response. Enhancement of the infected cells clearance as a second MoA was suggested for another protease inhibitor [6]. Such a VK model was used as a key element of a modeling and simulation framework to further support the development of DNV and potentially other DAA.
References:
[1] Snoeck E, Chanu P, Lavielle M, Jacqmin P, Jonsson E N, Jorga K, Goggin T, Grippo J, Jumbe N L and Frey N. A Comprehensive Hepatitis C Viral Kinetic Model Explaining Cure. ClinicalPharmacology & Therapeutics, Vol 87, Issue 6 (2010), 706-713
[2] Monolix, a free software dedicated to the analysis of non linear mixed effects models. (http://software.monolix.org/sdoms/software/)
[3] Adiwijaya BS, Hare B, Caron PR, Randle JR, Neumann AU, et al. Rapid decline of wild-type Hepatitis-C virus on telaprevir treatment. Antivir Ther (2009) 14:591-595.
[4] Foy E, Li K, Wang C, Sumpter Jr.R, Ikeda M, Lemon S.M, Gale Jr.M. Regulation of Interferon
Regulatory Factor-3 by the Hepatitis C Virus Serine Protease. Science 300, 1145 (2003)
[5] Liang Y, Ishida H, Lenz O, Lin TI, Nyanguile O, Simmen K, Pyles RB, Bourne N, Yi M, Li K ans Lemon SM. Antiviral Suppression vs Restoration of RIG-I Signaling by Hepatitis C Protease and Polymerase Inhibitors. Gastroenterology, 135: 1710-1718 (2008)
[6] Adiwijaya BS, Herrmann E, Hare B, Kieffer T, Lin C, Kwong AD, Garg V, Randle JCR, Sarrazin C, Zeuzem S, Caron PR. A Multi-Variant, Viral Dynamic Model of Genotype 1 HCV to Assess the in vivo Evolution of Protease-Inhibitor Resistant Variants. PLoS Comput Biol. (2010) Apr 15;6(4)
Reference: PAGE 21 (2012) Abstr 2444 [www.page-meeting.org/?abstract=2444]
Poster: Other Drug/Disease Modelling