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.
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.


METHODS
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.


CONCLUSIONS
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.
Department of Internal Medicine, University of Cologne, Cologne, Germany.
Gerd
G
Fätkenheuer
Schlomo
S
Staszewski
Andreas
A
Plettenburg
Frances
F
Hackman
Gary
G
Layton
Lynn
L
McFadyen
John
J
Davis
Tim M
TM
Jenkins
D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects*; D055815:Young Adult
D009570:Nitriles; D011720:Pyrazoles; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061