PI-73Effects of chronic hepatic impairment on the pharmacokinetics and safety of desvenlafaxine succinate extended release

Abstract

BACKGROUND/AIMS To assess the pharmacokinetics (PK) of desvenlafaxine in subjects with chronic hepatic impairment and matched healthy adults, following administration of desvenlafaxine succinate extended release (DVS). METHODS Hepatically impaired subjects (8 Child-Pugh class A, 8 Child-Pugh class B, and 8 Child-Pugh class C) and 12 matched healthy adults received 1 × 100-mg oral dose of DVS. Blood and urine samples were obtained over 96 hours and analyzed. A model-independent method was used to derive single-dose PK parameters of desvenlafaxine from plasma concentration vs time data. Statistical comparisons were made among groups using a 1-factor analysis of variance. RESULTS There were no statistically significant differences >50% for Cmax, AUCT, AUC∞ or CL/F of desvenlafaxine for hepatically impaired vs healthy subjects. Median Tmax of desvenlafaxine ranged from 6–9 hours and was similar for all groups. Mean Cmax of desvenlafaxine in hepatically impaired subjects was ≤25% higher than in healthy subjects. Mean AUC∞, CL/F and t1/2 of desvenlafaxine were similar for subjects with Child-Pugh A hepatic impairment and healthy subjects. There was a higher mean AUC∞, lower clearance, and longer t1/2in subjects with Child-Pugh B or C hepatic impairment. CONCLUSION Administration of single doses of DVS SR was safe and well tolerated in healthy and hepatically-impaired subjects. Moderate to severe hepatic impairment may alter the PK of DVS. Clinical Pharmacology & Therapeutics (2005) 79, P26–P26; doi: 10.1016/j.clpt.2005.12.094