Excretion and Metabolism of Lersivirine (5-{[3,5-Diethyl-1-(2- hydroxyethyl)(3,5-C2)-1H-pyrazol-4-yl]oxy}benzene-1,3- dicarbonitrile), a Next-Generation Non-Nucleoside Reverse Transcriptase Inhibitor, after Administration of [C]Lersivirine to Healthy Volunteers

Lersivirine [UK-453,061, 5-((3,5-diethyl-1-(2-hydroxyethyl)(3,5C2)-1H-pyrazol-4-yl)oxy)benzene-1,3-dicarbonitrile] is a nextgeneration non-nucleoside reverse transcriptase inhibitor, with a unique binding interaction within the reverse transcriptase binding pocket. Lersivirine has shown antiviral 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 500-mg dose of [C]lersivirine (parent drug) 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 h postdose. The majority of radioactivity was excreted in urine ( 80%) with the remainder excreted in the feces ( 20%). The blood/plasma ratio of total drug-derived radioactivity [area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf)] was 0.48, indicating that radioactive material was distributed predominantly into plasma. Lersivirine was extensively metabolized, primarily by UDP glucuronosyltransferaseand cytochrome P450-dependent pathways, with 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), whereas unchanged lersivirine represented 13% of total plasma radioactivity. In vitro studies showed that UGT2B7 and CYP3A4 are responsible for the majority of lersivirine metabolism in humans. The AIDS epidemic has reached pandemic proportions, culminating in the death of more than 2 million people in 2007 alone and resulting in 33 million people currently estimated as living with HIV/AIDS worldwide (UNAIDS/WHO, http://data.unaids.org/pub/ epislides/2007/2007_epiupdate_en.pdf). The widespread usage of highly active antiretroviral therapy since 1996 resulted in a substantial reduction in the mortality and morbidity of people infected with HIV (Palella et al., 1998). However, the emergence of drug-resistant viruses in patients treated with highly active antiretroviral therapy, together with the increasing transmission of these viruses in newly infected patients, has increased the demand for further therapeutic improvements (Cane et al., 2005; Daar and Richman, 2005). It is unfortunate that the three currently approved first-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) agents (efavirenz, nevirapine, and delavirdine) and the next-generation NNRTI etravirine all have side effects and/or drug interactions that limit their use for the treatment of HIV. In addition, all first-generation NNRTIs are susceptible to rapid-resistance generation through single-point mutations (Turpin, 2003). This research was sponsored by Pfizer Inc. and was conducted at Charles River Clinical Services Ltd., Edinburgh, United Kingdom. 1 Current affiliation: Drug Metabolism and Pharmacokinetics, Pharmaceutical Division, F. Hoffman-La Roche Ltd., Basel, Switzerland. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.109.031252. ABBREVIATIONS: NNRTI, non-nucleoside reverse transcriptase inhibitor; lersivirine/UK-453,061, 5-((3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol4-yl)oxy)benzene-1,3-dicarbonitrile; P450, cytochrome P450; ADME, absorption, distribution, metabolism, and excretion; [C]lersivirine, 5-{[3,5diethyl-1-(2-hydroxyethyl)(3,5-C2)-1H-pyrazol-4-yl]oxy}benzene-1,3-dicarbonitrile; HPLC, high-performance liquid chromatography; AUCinf, area under the plasma concentration-time profile from time zero extrapolated to infinite time; MS/MS, tandem mass spectrometry; AE, adverse event; rUGT, recombinant human UDP-glucuronosyltransferase; PF-04580552, 2-[4-(3,5-dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl b-D-glucopyranosiduronic acid; PF-03139905, 5-{[3-ethyl-5-(1-hydroxyethyl)-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}benzene-1,3-dicarbonitrile; UK-533,713, [4-(3,5-dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetic acid; UK-508,550, 5-{[5-ethyl-1,3-bis(2-hydroxyethyl)-1H-pyrazol-4yl]oxy}benzene-1,3-dicarbonitrile; PF-03230716, 5-{[5-ethyl-3-(1-hydroxyethyl)-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}benzene-1,3-dicarbonitrile; JNJ-10198409, 3-Fluoro-N-(6,7-dimethyoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamine. 0090-9556/10/3805-789–800$20.00 DRUG METABOLISM AND DISPOSITION Vol. 38, No. 5 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 31252/3577279 DMD 38:789–800, 2010 Printed in U.S.A. 789 at A PE T Jornals on D ecem er 9, 2017 dm d.aspurnals.org D ow nladed from