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Coadministration of BMS-790052 and BMS-650032 Does Not Result in a Clinically Meaningful Pharmacokinetic Interaction in Healthy Subjects
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Reported by Jules Levn
AASLD Nov 2 2010 Boston
Bifano M1, Sevinsky H,1 Bedford B,1 Coumbis J,1 Eley T,1 Huang SP,1 Medlock M,2 Grasela DM,1 Bertz R1
1Bristol-Myers Squibb, Research and Development, Hopewell, NJ, United States; 2PPD Development, LP, Austin, TX, United States.
Background: NS5A plays a central role in viral replication of hepatitis C virus (HCV). BMS-790052 is a first-in-class and potent NS5A Inhibitor with broad genotypic coverage. BMS-650032 is a potent HCV NS3 inhibitor with in vitro activity against genotypes 1a and 1b. Proof-of-concept multiple-dose studies in HCV subjects for each compound demonstrated a robust decline in HCV RNA when administered as monotherapy. Combinations of 2 or more direct-acting antiviral (DAA) agents are expected to be part of future HCV therapy; therefore, assessment of a potential drug-drug interaction with these 2 compounds together is warranted prior to commencement of clinical trials in HCV patients.
Methods: The objective of this open-label, randomized, multiple-dose study was to assess the pharmacokinetics (PK), safety, and tolerability of BMS-790052 and BMS-650032 when coadministered in healthy subjects for 14 days. Subjects received either 60 mg BMS-790052 QD or 600 mg BMS-650032 Q12h for 7 days during a lead-in period, followed by coadministration of 30 mg BMS-790052 QD and 200 mg BMS-650032 Q12h for 14 days. Plasma concentrations were obtained via liquid chromatography-tandem mass spectroscopy. Geometric mean ratios (GMR) and 90% confidence intervals (CI) for BMS-790052 and BMS-650032 PK were estimated by general linear mixed effects models.
Results: BMS-790052 and BMS-650032 exposures following respective doses of 30 mg QD and 200 mg Q12h administered together were comparable to historical data for similar doses of each compound administered alone. The GMR (90% CI) for BMS-790052 and BMS-650032 AUC[TAU] were 1.156 (0.895,1.491) and 1.025 (0.734,1.433), respectively. Following dose normalization to 60 mg, BMS-790052 exposure (AUC[TAU]) after coadministration of 30 mg QD with BMS-650032 200 mg Q12h for 14 days was similar to exposure observed following 7 days of BMS-790052 60 mg QD in the lead-in period, with a
GMR (90% CI) of 1.202 (1.113,1.298). Following dose normalization to 600 mg Q12h, BMS-650032 exposure (AUC[TAU]) after coadministration of 200 mg Q12h with BMS-790052 30 mg QD was similar to exposure observed in the lead-in period, with a GMR (90% CI) of 0.868 (0.726,1.038).
Conclusions: Coadministration of BMS-790052 and BMS-650032 in healthy subjects did not result in a clinically meaningful PK interaction; a clinically meaningful PK interaction is not anticipated when BMS-790052 and BMS-650032 are coadministered in HCV patients. Based on the results of this study, a clinical trial with BMS-790052 and BMS-650032, both with and without pegylated interferon/ribavirin, has commenced to assess the effect of dual NS5A plus NS3 inhibition in HCV therapy.
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