There was an approximate 30% increase in MDZ AUC when co-administered with MK-5172, suggesting that MK-5172 is a weak CYP3A4 inhibitor. There was an approximate 3-fold increase in atorvastatin AUC when co-administered with MK-5172, due to CYP3A4 inhibition and potentially BCRP inhibition. MK-5172 PK was not significantly impacted by co-administration with pitavastatin or atorvastatin. Disclosures: Luzelena Caro – Employment: Merck & Co., Inc. Jennifer E. Talaty- Employment: Merck, Sharp, & Dohme Zifang Guo – Employment: Merck & Co., Inc. Christina Reitmann – Employment: Merck, Sharp & Dohme, Corp Iain PF-01367338 clinical trial P. Fraser – Employment:
Merck & Co.; Stock Shareholder: Merck & Co. Raymond Evers – Employment: Merck Wendy W. Yeh – Employment: Merck & Co. Joan R. Butterton – Employment: Merck Sharp & Dohme Corp.; Stock Shareholder: Merck Sharp & Dohme Corp.
The following people have nothing to disclose: Dennis Swearingen Background: MK-5172, a once-daily competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease with improved potency compared with the approved first generation protease inhibitors, and MK-8742, a HCV NS5A replication complex inhibitor with improved potency compared to first generation NS5A inhibitors, are GDC-0068 in vitro being developed for the treatment of chronic HCV infection. Since these agents may be coadministered as a combination regimen for HCV, the present study evaluated the pharmacokinetic interactions and tolerability of MK-5172 and MK-8742 co-administration in healthy subjects. Methods: This was an open-label, multiple-dose study in 10 healthy adult male and female volunteers, ages 19-55 years. Since MK-5172 in
HCV-infected patients demonstrates ∼2-fold higher exposure compared to healthy subjects, a 200 mg dose of MK-5172 in healthy subjects was used in this study to match the exposure of 100 mg dose (the intended Phase 3 dose) in HCV-infected patients. In Period 1, subjects received oral doses of 200 mg MK-5172 once selleck chemicals llc daily on Days 1 to 7. Following a 7 day washout, subjects received oral doses of 20 mg MK-8742 once daily on Days 1 to 7 in Period 2. In Period 3, subjects were co-administered once daily oral doses of 200 mg MK-5172 and 20 mg MK-8742 on Days 1 to 8. Plasma PK samples were collected for the pharmacokinetic assessment of MK-5172 and MK-8742. Safety assessments included ECGs, vital signs, clinical laboratory tests, physical examination, and adverse event monitoring. Results: Co-administration of MK-5172 with MK-8742 was generally well-tolerated. Multiple oral doses of MK-5172 did not meaningfully change the steady-state AUC0-24h, Cmax, or C24h of MK-8742 with geometric mean ratios (GMRs) [90% confidence intervals (CIs)] for MK-8742 (MK-8742+MK-5172/MK-8742) of 1.01 [0.83, 1.24], 0.93 [0.76, 1.13], and 1.02 [0.83, 1.24], respectively. Multiple oral doses of MK-8742 did not meaningfully change AUC0-24h, Cmax, or C24h of MK-5172 (MK-5172+MK-8742/MK-5172) with GMRs [90% CIs] of 0.90 [0.