Clinical Therapeutics/Volume 32, Number 11, 2010 October 2010 1889 The study findings were presented in a poster at the 15th Conference on Retroviruses and Opportunistic Infections, February 3–6, 2008, Boston, Massachusetts. Accepted for publication September 16, 2010. doi:10.1016/j.clinthera.2010.10.007 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved. ABSTRACT Background: Lersivirine is a nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1. Objective: The goal of this study was to investigate the safety and tolerability of multiple oral doses of lersivirine administered to healthy male subjects to assist in the planning of longer term studies. Methods: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter, Phase I clinical study in fasting, healthy male volunteers. Subjects were randomly assigned in a ratio of 7:7:4:4 to receive lersivirine 500 mg BID, lersivirine 750 mg once daily, efavirenz 600 mg once daily, or placebo once daily for 28 days. Safety and tolerability were assessed throughout the study by continuous collection of adverse events (AEs), includ- ing adverse drug reactions, illnesses with onset during the study, exacerbation of previous illnesses, and clini- cally significant changes in physical examination find- ings. Vital sign measurements and ECGs were performed at screening; on day 1 (predose and 2, 3, and 4 hours postdose); on days 7, 14, 21, and 28 (predose); at discharge; and at follow-up. Safety laboratory tests (including hematology, chemistry, and urinalysis) were performed at screening; days 0, 7, 14, 21, and 27; and at follow-up. Results: Of the 66 healthy male subjects enrolled (age range, 21–51 years; body mass index, 18.1– 29.9 kg/m 2 ), 40 were white, 22 were Asian, 3 were black, and 1 was of mixed race. There were no clini- cally significant laboratory abnormalities, including changes in lipid profile, liver or renal function test results, or ECG findings. Overall, 86% (18/21) of subjects in the lersivirine 500-mg BID group, 81% (17/21) in the lersivirine 750-mg once-daily group, 92% (11/12) in the efavirenz 600-mg once-daily group, and 92% (11/12) in the placebo group experienced at least one treatment-related AE. Eight subjects were permanently discontinued from the study; 4 subjects in the efavirenz group (3 of whom participated in the trial at the Brussels study center) were permanently discontinu- ed due to AEs considered to be treatment related. No subjects receiving lersivirine permanently discontinued the study due to treatment-related AEs, although one subject temporarily discontinued treatment. In addi- tion, 4 subjects withdrew consent (2 subjects [1 of whom was at the Brussels study center] receiving lersivirine 750 mg once daily and 2 subjects [1 of whom was at the Brussels study center] receiving efavirenz). There were no deaths or serious AEs in any of the study groups. Conclusion: Lersivirine appeared to be well tolerated after 28 days of continuous dosing in this small, selected group of young, healthy male volunteers. (Clin Ther. 2010;32:1889–1895) © 2010 Excerpta Medica Inc. Key words: lersivirine, safety, adverse events, NNRTI, healthy volunteers. Safety and Tolerability of Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor, During a 28-Day, Randomized, Placebo-Controlled, Phase I Clinical Study in Healthy Male Volunteers John Davis, PhD 1 ; Frances Hackman, MSc 1 ; Marie-Noella Ndongo, MD 2 ; HengWee Choo, MD 3 ; Drew Lewis, MD 4 ; Margaret Tawadrous, MD 5 ; James Goodrich, PhD, MD 6 ; and Grant Langdon, PhD 1 1 Pfizer Inc, Sandwich, United Kingdom; 2 Pfizer Clinical Research Unit, Erasme, Brussels, Belgium; 3 Pfizer Clinical Research Unit, Singapore General Hospital, Singapore; 4 Pfizer Inc, New York, New York; 5 Pfizer Inc, New London, Connecticut; and 6 ViiV Healthcare, Research Triangle Park, North Carolina