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 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.
Sadler
B M
BM
Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA. bms44974@glaxowellcome.com
Hanson
C D
CD
Chittick
G E
GE
Symonds
W T
WT
Roskell
N S
NS
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D001682:Biological Availability; D002219:Carbamates; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D016333:HIV Protease