These results suggest that no dose adjustments of MK-5172 or daclatasvir are needed for co-administration of these drugs in HM781-36B interferon-free, combination regimens containing these once-daily direct acting antivirals in HCV-infected patients. Disclosures: Wendy W. Yeh – Employment: Merck & Co. Iain P. Fraser – Employment: Merck & Co.; Stock Shareholder: Merck & Co. Marc Bifano – Employment: Bristol-Myers Squibb Luzelena Caro – Employment: Merck & Co., Inc. Jennifer E. Talaty – Employment: Merck, Sharp, & Dohme Zifang Guo – Employment: Merck & Co., Inc. Stephen P. Youngberg – Employment: Celerion, Inc. Joan R. Butterton
– Employment: Merck Sharp & Dohme Corp.; Stock Shareholder: Merck Sharp & Dohme Corp. The following people have nothing to disclose: Jennifer M. McCarthy Background Sofosbuvir (SOF) is a specific nucleotide HCV NS5B polymerase
inhibitor. GS-5816 is a second generation HCV NS5A inhibitor with picomolar antiviral activity against genotypes 1-6. The combination of SOF and GS-5816 may constitute a regimen with broad genotypic activity for the treatment of patients with chronic HCV infection. Thus, a drug-drug interaction study between SOF and GS-5816 was conducted in healthy volunteers. Methods In this open-label, fixed-sequence, cross-over, drug-drug interaction study, subjects received a single dose (SD) of SOF 400 mg on Day 1, once-daily doses of GS-5816 150 mg on Days 5-13, and a SD of SOF 400 mg coadministered
with GS-5816 LY294002 manufacturer 150 mg on Day 14. All doses were administered under fed conditions. Safety assessments were performed throughout the study. Geometric means ratios (GMR%: combination vs. alone) and 90% confidence intervals (CIs) for AUCinf and Cmax of SOF and GS-331007 (the predominant circulating nucleoside metabolite of SOF) and AUC-tau, Cmax and Ctau of GS-5816 were estimated using Metalloexopeptidase ANOVA. Lack of pharmacokinetic (PK) interaction bounds were set as 70% to 143%. Results All enrolled subjects (N=18) completed the study. Study drugs were generally well tolerated. Three subjects receiving SOF alone, 3 subjects receiving GS-5816 alone, and 4 subjects receiving SOF+GS-5816 experienced a treatment-emergent adverse event (AEs). All AEs were Grade 1 (mild); one AE (constipation) was considered study drug-related. GMR% (90% CI) upon coadministration vs. treatment alone are presented in the table below. SOF plasma exposure increased ∼1.8-2.4-fold when coadministered with GS-5816. The effect of GS-5816 on SOF is likely due to inhibition of intestinal P-gp and/or BCRP, of which SOF is a known substrate. The magnitude of the increase in exposure for SOF was comparable to that seen when SOF was coadministered with the first-generation NS5A inhibitor ledipasvir. For GS-331007, an approximately 35% lower Cmax was observed upon SOF administration with GS-5816. The GMR% (90% CI) for GS-331007 AUC were within the equivalence bounds.