Mayu Osawa (1), Takayo Ueno (1), Tomoko Ueki (1), Yasuhiko Imai (1), Phyllis Chan (2), Tushar Garimella (2), Timothy Eley (2), Malaz AbuTarif (2), Richard Bertz (2)
(1) Bristol-Myers K.K., Research and Development, Tokyo, Japan (2) Bristol-Myers Squibb, Research and Development, NJ, USA
Objectives: The approval of the combination therapy of Daclatasvir (DCV) and Asunaprevir (ASV) in Japan represented the world’s first approval of an interferon and rebavirin-free Hepatitis C Virus (HCV) treatment. The objectives of these analyses were to develop the DCV and ASV population pharmacokinetic (popPK) models for estimating the effects of demographic, pathopysiologic, and disease-related covariates for Japanese HCV patients and providing individual patient PK parameter estimates for subsequent exposure-response analysis.
Methods: These popPK models were developed with FOCE-I in NONMEM V7.2.0 from four (DCV) and two (ASV) Phase 2/Phase 3 studies in Japanese subjects with HCV infection. The ASV tablet formulation was used for Phase2 study. To improve the oral bioavailability and mitigate food effect, the ASV softgel capsule formulation was developed for Phase 3 study. Total individuals included in the analysis for DCV and ASV were 336 and 265, respectively. A one-compartment model was selected as the structural model based on model development work. The full-covariate model was developed by incorporating the effects of all pre-specified covariates on structural model parameters. Highly correlated covariates were screened and the one showing the largest decrease in OFV compared to base model was retained in full model. The final model was developed by backward elimination from the full model. Model evaluation was conducted using visual predictive check and bootstrap.
Results: Significant covariates for DCV included gender, treatment description and creatinine clearance on CL/F and body weight on V/F, and for ASV included baseline and time-varying aspartate aminotransferase (AST) and cirrhosis on CL/F, formulation on CL/F and V/F. The final model indicated that worsening of hepatic status (presence of cirrhosis and increase in AST) led to decrease in ASV CL/F. The bioavailability of the softgel capsule formulation of ASV was higher than the tablet formulation. The effects of all covariate effects for DCV PK in the final model were within or overlapped the 80-125% difference from typical value.
Conclusions: The popPK models adequately described the PK profiles of DCV and ASV in Japanese subjects with HCV infection.The magnitude of estimated covariate effects on DCV PK were small and not clinically meaningful. ASV CL/F decreased with cirrhosis and increasing baseline and time-varying AST indicating an association between hepatic markers and ASV CL/F.
Reference: PAGE 24 () Abstr 3315 [www.page-meeting.org/?abstract=3315]
Poster: Drug/Disease modeling - Infection