title: 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.
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), including adverse drug reactions, illnesses with onset during the study, exacerbation of previous illnesses, and clinically significant changes in physical examination findings. 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 clinically 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 discontinued 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 addition, 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.
  
  
  CONCLUSIONS
  Lersivirine appeared to be well tolerated after 28 days of continuous dosing in this small, selected group of young, healthy male volunteers.
authors.affiliation: Research Clinical Pharmacology, Pfizer Inc, Sandwich, Kent, United Kingdom. john.davis@pfizer.com
authors.forename: John
authors.initials: J
authors.lastname: Davis
authors.forename: Frances
authors.initials: F
authors.lastname: Hackman
authors.forename: Marie-Noella
authors.initials: MN
authors.lastname: Ndongo
authors.forename: HengWee
authors.initials: H
authors.lastname: Choo
authors.forename: Drew
authors.initials: D
authors.lastname: Lewis
authors.forename: Margaret
authors.initials: M
authors.lastname: Tawadrous
authors.forename: James
authors.initials: J
authors.lastname: Goodrich
authors.forename: Grant
authors.initials: G
authors.lastname: Langdon
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D048588:Benzoxazines / Q000009:adverse effects; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; C098320:efavirenz