GW420867X administered to HIV-1-infected patients alone and in combination with lamivudine and zidovudine.
OBJECTIVE
GW420867X is a nonnucleoside inhibitor of HIV-1 reverse transcriptase. The primary objective was to assess the safety of GW420867X in HIV-1-infected patients. The secondary objectives were to assess the effect of GW420867X on plasma HIV-1 RNA and viral genotype and phenotype and to examine the pharmacokinetics of GW420867X in HIV-1-infected patients.


METHODS
HIV-1-infected patients were randomized to GW420867X 50 mg/day, 100 mg/day, or 200 mg/day from days 1-28 (n = 15 per group). Lamivudine (3TC) plus zidovudine (ZDV) was added from days 8-28. A control group (n = 15) received GW420867X, 3TC, and ZDV placebos.


RESULTS
Plasma HIV-1 RNA and CD4+ counts improved in the GW420867X groups at days 8 and 28. No significant development of drug resistance was detected. Median observed peak GW420867X concentration (C(max)) generally occurred at 2 hours. The area under the curve over the dosing interval (AUCtau)on day 14 increased less than proportionally to dose, suggesting there was increased clearance and/or decreased absorption. Mean trough GW420867X concentrations were many fold above the in vitro IC(50) in the presence of human serum proteins. Seven of 15 patients on 50 mg GW420867X, 8/15 on 100 mg GW420867X, 12/15 on 200 mg GW420867X, and 8/15 on placebo reported drug-related adverse events.


CONCLUSIONS
GW420867X was well tolerated and has potent antiretroviral activity alone and in combination with 3TC plus ZDV.
Arasteh
K
K
EPIMED-Auguste-Viktoria-Hospital, Berlin, Germany. arasteh@avk.b.shuttle.de
Wood
R
R
Müller
M
M
Prince
W
W
Cass
L
L
Moore
K H
KH
Dallow
N
N
Jones
A
A
Klein
A
A
Burt
V
V
Kleim
J P
JP
D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011810:Quinoxalines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; C402066:GW420867X; D011810:Quinoxalines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine