We conducted a double-blind, placebo-controlled, parallel, dose-escalation trial to evaluate the pharmacokinetics and safety of single, oral doses of
amprenavir (141W94; formerly
VX-478), a potent inhibitor of human immunodeficiency virus (HIV) type 1
protease, administered as hard
gelatin capsules in 12 HIV-infected subjects. The doses of
amprenavir evaluated were 150, 300, 600, 900, and 1,200 mg.
Amprenavir was rapidly absorbed, with the time to maximum concentration occurring within 1 to 2 h after dosing. On the basis of power model analysis, the increase in the maximum concentration of
amprenavir in plasma (Cmax) was less than dose proportional, and the increase in the area under the concentration-time curve from time zero to infinity (AUC0-infinity) was greater than dose proportional; mean slopes (with 90% confidence intervals) were 1.25 (1.16 to 1.35) and 0.78 (0.78 to 0.86) for AUC0-infinity and Cmax, respectively.
Amprenavir was eliminated slowly, with a terminal-phase half-life of 8 h. A second study was conducted to determine the bioavailability of the hard
gelatin capsule relative to that of a subsequently developed soft
gelatin capsule. The capsules were bioequivalent in terms of AUC0-infinity but not in terms of Cmax; geometric-least-squares means ratios (with 90% confidence intervals) were 1.03 (0.92 to 1.14) and 1.25 (1.03 to 1. 53) for AUC0-infinity and Cmax, respectively. Administration of soft
gelatin capsules of
amprenavir with a high-fat breakfast resulted in a 14% decrease in the mean AUC0-infinity (from 9.58 to 8.26 microg. h/ml), which is not likely to be clinically significant. The most common adverse events related to
amprenavir were
headache,
nausea, and
hypesthesia.
Amprenavir appears to be safe and well tolerated over the dose range of 150 to 1200 mg. On the basis of the present single-dose studies,
amprenavir is an
HIV protease inhibitor with favorable absorption and clearance pharmacokinetics that are only minimally affected by administration with food.