Safety and pharmacokinetics of amprenavir (141W94), a human immunodeficiency virus (HIV) type 1 protease inhibitor, following oral administration of single doses to HIV-infected adults

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 immunodef iciency virus (HN) type 1 protease, administered as hard gelatin capsules i n 12 HN-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 ampre navir in plasma (C-max) was less than dose proportional, and the increase i n the area under the concentration-time curve from time zero to infinity (A UC(0-infinity)) was greater than dose proportional; mean slopes (with 90% c onfidence intervals) were 1.25 (1.16 to 1.35) and 0.78 (0.78 to 0.86) for A UC(0-infinity) and C-max, respectively. Amprenavir was eliminated slowly, w ith a terminal-phase half-life of 8 h, A second study was conducted to dete rmine the bioavailability of the hard gelatin capsule relative to that of a subsequently developed soft gelatin capsule. The capsules were bioequivale nt in terms of AUC(0-infinity) but not in terms of C-max; geometric-least-s quares means ratios (with 90% confidence intervals) were 1.03 (0.92 to 1.14 ) and 1.25 (1.03 to 1.53) for AUC(0-infinity) and C-max respectively. Admin istration of soft gelatin capsules of amprenavir with a high-fat breakfast resulted in a 14% decrease in the mean AUC(0-infinity) (from 9.58 to 8.26 m u g . h/ml), which is not likely to be clinically significant. The most com mon adverse events related to amprenavir were headache, nausea, and hypesth esia, 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, amprena vir is an HIV protease inhibitor with favorable absorption and clearance ph armacokinetics that are only minimally affected by administration with food .