Excretion and Metabolism of Lersivirine (UK-453,061), a Next Generation NNRTI, Following Administration of [14C] Lersivirine to Healthy Volunteers

Lersivirine (UK-453,061) is a next-generation non-nucleoside reverse transcriptase inhibitor, with a unique binding interaction within the reverse transcriptase binding pocket. Lersivirine has demonstrated anti-viral activity and is well-tolerated in HIV-infected and healthy subjects. This open-label, Phase I study investigated the absorption, metabolism, and excretion of a single oral dose of [14C] lersivirine (parent drug) 500 mg, and characterized the plasma, fecal, and urinary radioactivity of lersivirine and its metabolites in four healthy male volunteers. Plasma Cmax for total radioactivity and unchanged lersivirine typically occurred between 0.5 and 3 hours postdose. The majority of radioactivity was excreted in urine (~80%), with the remainder in the feces (~20%). The blood:plasma ratio of total drug derived radioactivity (AUCinf) was 0.48, indicating that radioactive material was distributed predominantly into plasma. Lersivirine was extensively metabolized, primarily by UDP-glucuronsyltransferase and cytochrome P450 dependent pathways, with a total of 22 metabolites being identified in this study. Analysis of precipitated plasma revealed that the lersivirine-glucuronide conjugate was the major circulating component (45% of total radioactivity) whilst unchanged lersivirine represented 13% of total plasma radioactivity. In vitro studies demonstrated that UGT 2B7 and CYP 3A4 are responsible for the majority of lersivirine metabolism in humans.