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Short-Course Monotherapy with AG1549, a Novel Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), in Antiretroviral Naïve Patients J. HERNANDEZ*1, L. AMADOR1, M. AMANTEA2, H. CHAO2, P. HAWLEY2, and L. PARADISO2.
1Immunity Care & Res., Inc., Plantation, FL; and 2Agouron Pharmaceuticals, Inc., La Jolla, CA AG1549, an investigational NNRTI with a novel resistance profile, exhibits potent antiviral activity against HIV variants with RT substitutions, including K103N, which confer broad cross-resistance among the approved NNRTIs. This study evaluated the safety, pharmacokinetics (PKs) and dynamics of HIV elimination with 10-day monotherapy with AG1549, formerly known as S-1153, licensed by Agouron Pharmaceuticals, Inc. from Shionogi & Co., Ltd.
Doses were administered orally at 700, 1400 or 2100 mg BID or 700 or 1400 mg TID in 5 separate arms to HIV infected, antiretroviral naïve patients. Total daily doses ranged from 1400 mg to 4200 mg. The PKs of AG1549 were studied on Days 1, 5, and 10 for each of the dosing arms, and daily viral load measurements were performed. A control arm was treated with nelfinavir (NFV) and AZT/3TC. Six patients were entered into each arm.
AG1549 was well tolerated at all doses. The most commonly reported treatment emergent drug-related adverse events were nausea, vomiting and headache. There were no serious adverse events. AG1549 displayed linear PKs with a half-life of ~ 2 hours; the mean (CV%) maximum and minimum steady-state plasma concentrations across dosing arms ranged from 2.22 (42.3) to 6.65 (37.4) mg/L and 0.0475 (51.3) to 0.417 (31.4) mg/L, respectively. Over the 10 days of the study comparable decreases in viral load were exhibited across all study arms. Mean decreases in viral load ranged from 1.23 logs for the 700 mg BID arm to 1.69 logs for the 2100 mg BID arm whereas a mean decrease of 1.65 logs was observed in the NFV/AZT/3TC study arm. BID and TID arms had similar viral load elimination.
AG1549 demonstrates potent antiviral activity and good tolerability at all doses tested over the 10 day duration of this trial.
Key Words: NNRTI, pharmacokinetics, viral kinetics
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