Age and Gender Effects on the Pharmacokinetics of HCV NS5A Inhibitor MK-8742

Background: MK-8742 is a potent, once-daily, inhibitor of the hepatitis C virus (HCV) nonstructural protein NS5A being developed for the treatment of chronic HCV infection. This study was the first comparison of MK-8742 pharmacokinetics (PK) between males and females, as well as the first comparison between healthy young males and healthy elderly subjects. Methodology: This was a double-blind, placebo-controlled, randomized, single-dose study designed to evaluate the safety, tolerability, and PK of MK-8742 in healthy elderly male and female subjects. Panel A and Panel B consisted of 14 healthy elderly male (age 65-78 years) and 14 healthy elderly female (age 65-80 years) subjects, respectively. Twelve (12) subjects per panel were randomized to receive a single oral dose of 100 mg MK-8742, and 2 subjects per panel received matching placebo. Panel C consisted of 8 young (age 22-45 years) male subjects; 6 received MK-8742 and 2 received placebo. Results: A single dose of 100 mg MK-8742 was well tolerated in the healthy elderly males and females and healthy young males in this study. The MK-8742 AUC0-∞, Cmax, and C24h geometric mean ratios (GMRs) (90% confidence intervals [90% CIs]) for the comparison of a single dose of 100 mg MK-8742 administered to healthy elderly females vs healthy elderly male subjects were 1.67 (1.12, 2.48), 1.75 (1.16, 2.66) and 1.58 (1.07, 2.33), respectively. Additional exploratory analyses were conducted to adjust for body weight or BMI. The resulting AUC0-∞ GMRs (90% CIs) for the comparison of a single dose of 100 mg MK-8742 administered to healthy elderly female vs healthy elderly male subjects were 1.33 (0.83, 2.14), when adjusted for body weight, and 1.64 (1.10, 2.45), when adjusted for BMI. Similar results were obtained for the Cmax and C24h parameters following these additional analyses. The MK-8742 AUC0-∞, Cmax, and C24h GMRs (90% CIs) for the comparison of a single dose of 100 mg MK-8742 administered to healthy elderly males vs healthy young males were 1.02 (0.69, 1.53), 0.91 (0.60, 1.38), and 0.97 (0.66, 1.44). Conclusions: The plasma exposures following a single 100 mg dose of MK-8742 in healthy elderly female subjects is approximately 70% greater than that observed in healthy elderly male subjects. The plasma AUC0-∞ is approximately 33% greater in healthy elderly female subjects when adjusted for weight, suggesting that the observed gender effect may partially be explained by gender differences in body weight. A single 100 mg administration of MK-8742 results in similar exposures in healthy elderly male and healthy young male subjects. MK-8742 was well tolerated in the healthy elderly male and female subjects in this study. Background • MK-8742 is a potent, once-daily inhibitor of the hepatitis C virus (HCV) nonstructural protein NS5A being developed for the treatment of chronic HCV infection in mono- and HCV/human immunodeficiency virus (HIV)-coinfected patients. • This study represented the first comparison of MK-8742 PK between healthy elderly males and females, providing preliminary safety data for this study population age group in HCV-infected patients, as well as the first comparison between healthy young males and healthy elderly subjects. • MK-8742, a hepatitis C virus (HCV) NS5A inhibitor with potent activity against several HCV genotypes, is being developed as a potential component of an all-oral, direct-acting antiviral regimen. It is currently in Phase 3 development for use in in combination with MK-5172, an HCV NS3/4A protease inhibitor, for the treatment of chronic HCV infection.