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Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection

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Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection Infect Dis Ther https://doi.org/10.1007/s40121-018-0197-y ORIGINAL RESEARCH Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection Li Zhu . Hanbin Li . Phyllis Chan . Timothy Eley . Yash Gandhi . Marc Bifano . Mayu Osawa . Takayo Ueno . Eric Hughes . Malaz AbuTarif . Richard Bertz . Tushar Garimella Received: February 15, 2017 Ó The Author(s) 2018 ABSTRACT Results: A two-compartment model with first- order elimination from the central compart- Introduction: Asunaprevir (ASV) is a potent, ment, an induction effect on clearance, and an pangenotypic, twice-daily hepatitis C virus absorption model consisted of zero-order release (HCV) NS3 inhibitor indicated for the treatment followed by first-order absorption adequately of chronic HCV infection. described ASV PK after oral administration. A F Methods: A population pharmacokinetic (PPK) typical value for ASV clearance (CL/ ) was 50.8 F model was developed using pooled ASV con- L/h, increasing by 43% after 2 days to a CL/ of centration data from 1239 HCV-infected sub- 72.5 L/h at steady-state, likely due to auto-in- jects who received ASV either as part of the duction of cytochrome P450 3A4 (CYP3A4). DUAL regimen with daclatasvir or as part of the Factors indicative of hepatic function were QUAD regimen with daclatasvir and peg-inter- identified as key influential covariates on ASV feron/ribavirin. exposures. Subjects with cirrhosis had an 84% increase in ASV area under the concentration time curve (AUC) and subjects with baseline aspartate aminotransferase (AST) above 78 IU/L Enhanced content To view enhanced content for this had a 58% increase in area under the concen- article go to https://doi.org/10.6084/m9.figshare. tration time curve (AUC). Asians subjects had a 5966257. 46% higher steady-state AUC relative to White/ Caucasian subjects. Other significant covariates Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40121- were formulation, age, and gender. 018-0197-y) contains supplementary material, which is Conclusion: The current PPK model provided a available to authorized users. parsimonious description of ASV concentration data in HCV-infected subjects. Key covariates & L. Zhu Á P. Chan Á T. Eley Á Y. Gandhi ( ) Á identified in the model help explain the M. Bifano Á E. Hughes Á M. AbuTarif Á R. Bertz Á T. Garimella observed variability in ASV exposures and may Bristol-Myers Squibb Research and Development, guide clinical use of the drug. Lawrenceville, NJ, USA Funding: Bristol-Myers Squibb. e-mail: [email protected] M. Osawa Á T. Ueno Keywords: Asunaprevir; Direct-acting Bristol-Myers Squibb K K, Tokyo, Japan antivirals; Hepatitis C infection; NS3 protease H. Li inhibitors; Population pharmacokinetics Quantitative Solutions, Menlo Park, CA, USA Infect Dis Ther INTRODUCTION recommended to be used in these subjects. Asunaprevir exposure was also higher with Chronic hepatitis C virus (HCV) infection, cur- increased aspartate aminotransferase (AST), rently estimated to affect about 3% of world alanine aminotransferase (ALT) and total population, or 80–185 million people, frequently bilirubin levels, and decreased albumin levels leads to hepatocellular carcinoma, cirrhosis, and [14]. Furthermore, cross-study comparisons of liver transplantation [1, 2]. Asunaprevir (for- steady-state ASV exposures from subjects with merly BMS-650032, ASV) is a tripeptidic acylsul- HCV infection indicated approximately 2- to fonamide inhibitor of the HCV NS3/4A protease 3-fold higher exposure than those from healthy [3, 4]. Asunaprevir is approved for the treatment subjects [9]. Inflammation, tissue damage and of chronic HCV in multiple countries as part of fibrosis associated with chronic HCV infection the all-oral direct-acting antiviral (DAA) DUAL could affect liver uptake of ASV and/or reduce combination regimen with the HCV NS5A inhi- hepatic CYP3A4 activity, resulting in decreased bitor daclatasvir (DCV) or part of the QUAD clearance of the drug [15]. regimen with DCV and peginterferon/ribavirin Ethnic differences have been reported in ASV (pegINF/RBV) in patients with genotype 1 or exposure. In Phase II studies, ASV maximum genotype 4 HCV [5–8]. concentration (Cmax) and AUC in Japanese Asunaprevir has shown complex pharma- subjects were approximately double compared cokinetic (PK) characteristics [9]. The dose–ex- to White subjects [16]. Data in Chinese and posure relationship for ASV is generally non- Indian subjects also suggested that exposure in linear. In multiple ascending dose (MAD) stud- these populations was closer to that observed in ies, ASV administered using an early capsule Japanese subjects than observed in Caucasian formulation resulted in greater-than-dose-pro- subjects. Body weight may be a contributing portional increases in exposure from 10 to factor; however, there was a high degree of 600 mg twice daily (BID) [10]. overlap in body weights between the Asian and Asunaprevir is eliminated primarily via White subjects in these clinical studies. cytochrome P450 (CYP) 3A4-mediated hepatic Significant food effects has been observed metabolism, whereas distribution of asunapre- with a tablet formulation used in Phase I/II vir to the liver occurs via organic anion-trans- studies [9]. A soft-gel capsule, developed as a porting polypeptide (OATP) [11–13]. food-effect-mitigating formulation, is able to Asunaprevir displays time-dependent nonlinear provide significantly higher exposures (approx- pharmacokinetics. Following multiple doses at imately 4- to 5-fold for Cmax and 2-fold for AUC) 400 and 600 mg BID, ASV trough concentra- with or without food than the tablet formula- tions were lower on Day 14 compared to Day 1, tion given with food [17]. Subsequently, the suggesting auto-induction of CYP3A4. The soft-gel capsule was used in Phase III studies magnitude of auto-induction appeared to be without food restrictions and is the commercial dose-dependent. At the 200 mg BID, the trough formulation [5]. concentration ratio of Day 14 to Day 1 was 1.9, A population PK analysis was conducted suggesting a more modest auto-induction. This using data pooled from select Phase II/III studies is consistent with the weak inductive effect of to help better understand the complex PK pro- asunaprevir on midazolam, a sensitive CYP3A4 file and the exposure of ASV in subjects with probe substrate [13]. chronic HCV infection at clinically relevant Hepatic function impairment had been doses. More importantly, the analysis helps shown to significantly impact the steady-state explain the sources of variability in ASV expo- PK of ASV [14]. Asunaprevir exposures were sures by investigating potential relationships approximately 5- to 10- and 20- to 30-fold between covariates and PK parameters of ASV in higher in subjects with moderate (Child–Pugh the target patient population. The model would B) and severe (Child–Pugh C) hepatic impair- also provide individual post hoc predicted ment, respectively, and as such ASV is not exposure values for subsequent exposure–re- sponse analyses. Infect Dis Ther METHODS Model selection was based on significant reduction in the objective function value (OFV; Clinical Studies and Patient Population p \ 0.05), precision and plausibility of parame- ter estimates, and goodness-of-fit plots. Once the structural base model was identi- Asunaprevir concentration, time data were fied, covariate evaluations were performed to obtained from 3 Phase II and 2 Phase III studies, assess the influence of key patient and treat- among which 1 Phase II and 1 Phase III studies ment characteristics on the PK of ASV. Covari- were in Japanese subjects (Supplemental Table 1 ate model building was conducted with the full in the Electronic Supplementary Material). model approach [18]. Covariates were added to Asunaprevir was administered either as part of the base model in a univariate fashion; and the DUAL regimen with DCV or as part of the significant covariate-PK relationships were QUAD regimen with DCV and pegINF/RBV. The evaluated using the log-likelihood ratio test asunaprevir doses investigated were 100, 200 (LRT). All significant (p \ 0.05) covariates were and 600 mg, given once daily (QD) or BID, included in the full model. The selection of either in tablet or soft-gel formulation. Eligible covariates and likely impacted PK parameters subjects were male or female C 18 years of age, was based on clinical interest, pharmacological with chronic HCV genotype 1 and 4 infections. plausibility, prior knowledge and the availabil- Subjects with compensated cirrhosis and mild ity of data. As baseline AST and ALT were highly hepatic impairment were included. Subjects correlated (r2 = 0.86), only the most significant could be treatment naive, partial, null respon- term was kept in the full model if both covari- ders or ineligible/intolerant to the pegINF/RBV- ates were found to be significant in the uni- based therapy. variate screening. On-treatment AST and ALT values were also investigated as time-varying Compliance with Ethics Guidelines covariates on ASV CL/F, as treatments would This article is based on previously conducted normalize hepatic functions. Asunaprevir dose studies and does not contain any studies with was investigated as a covariate on the relative human participants or animals performed by bioavailability (F) based on the observed non- any of the authors. linear dose–exposure relationship in the MAD study. Population Pharmacokinetic Analysis The final model was obtained using a step- wise backward elimination process to reach a Model Development parsimonious model. The covariate with the The population PK model development was smallest change in objective function was comprised of establishing a base, full and final removed from the model, and the process model. The base structural model development repeated until all remaining covariates were was guided by the graphical evaluation of ASV significant at p \ 0.001 based on LRT. Uncer- plasma concentration–time profiles. Also tainties in the final model parameter estimates investigated as part of the base model were were reported with stratified nonparametric fixed-effect parameters associated with ASV bootstrap 95% confidence intervals (CI) [19].
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