Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patients.

Abstract

OBJECTIVE:

To investigate the effects on viral load and assess dose-response relationships, pharmacokinetics, safety and tolerability of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, in asymptomatic HIV-1-infected patients.

DESIGN:

Randomized, double-blind, placebo-controlled, parallel group, multicenter phase IIa clinical study.

METHODS:

Forty-eight HIV-1-infected patients were enrolled for the study of once-daily or twice-daily lersivirine at total daily doses ranging from 20 to 1000 mg. The primary endpoint was the change in log10 plasma HIV-1 RNA viral load from baseline to day 8. Secondary endpoints related to pharmacokinetics, safety and tolerability and potential development of viral resistance and genotyping patterns.

RESULTS:

Patients treated with lersivirine achieved day 8 mean viral load reductions of 0.3, 0.8, 1.3 and 1.6 log10 after receiving 10, 30, 100 and 500 mg twice daily, respectively, and 0.9, 1.7 and 1.8 log10 after receiving 100, 500 and 750 mg once daily, respectively. Mean changes from baseline to day 8 were small in patients receiving placebo. For all dose regimens, plasma exposure increased approximately in line with lersivirine dose. Median plasma concentrations of lersivirine at steady state were above the IC90 for lersivirine at once-daily doses of at least 500 mg and twice-daily doses of at least 100 mg. The most commonly reported treatment-emergent adverse events were headache, fatigue and nausea.

CONCLUSION:

Seven-day monotherapy with lersivirine achieved mean viral load reductions up to 1.8 log10. Lersivirine was safe and well tolerated. Further studies of lersivirine in combination with other antiretroviral drugs to assess long-term durability of antiviral response, safety and tolerability are warranted.

• Authors: Gerd Fätkenheuer, Schlomo Staszewski, Andreas Plettenburg, Frances Hackman, Gary Layton, Lynn McFadyen, John Davis, Tim M Jenkins
• Journal: AIDS (London, England) (AIDS) Vol. 23 Issue 16 Pg. 2115-22 (Oct 23 2009) ISSN: 1473-5571 [Electronic] England
• PMID: 19779321 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Nitriles
• Pyrazoles
• RNA, Viral
• Reverse Transcriptase Inhibitors
• UK 453,061

Topics

• Adolescent
• Adult
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• HIV Infections (drug therapy, metabolism, virology)
• HIV-1 (drug effects)
• Humans
• Male
• Middle Aged
• Nitriles (adverse effects, pharmacokinetics, therapeutic use)
• Pyrazoles (adverse effects, pharmacokinetics, therapeutic use)
• RNA, Viral (blood)
• Reverse Transcriptase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Viral Load (drug effects)
• Young Adult