Steady-state pharmacokinetics of atazanavir given alone or in combination with saquinavir hard-gel capsules or amprenavir in HIV-1-infected patients.
OBJECTIVE
The aim of this pilot study was to examine the pharmacokinetics of atazanavir (ATV) when given in combination with amprenavir (APV) or saquinavir hard-gel capsules (SQV) to human immunodeficiency virus (HIV)-positive patients.


METHODS
Included in the study were 34 HIV-infected patients enrolled in the ATV Early Access Program, who were treated with unboosted ATV alone (group 1) or with the double protease inhibitor combinations, ATV plus APV (group 2) or ATV plus SQV (group 3). ATV was given at a daily dose of 400 mg q.d. with the morning meal with SQV 1200 mg per day or APV 1200 mg per day. Serial blood samples for steady-state ATV pharmacokinetics were collected before the morning dose and at 1, 2, 3, 6, 8 and 24 h post-dosing. ATV plasma concentrations were measured using a high-performance liquid chromatography method with ultraviolet detection.


RESULTS
Of the patients, 12 received ATV as a single protease inhibitor; 12 received ATV in combination with APV; and 10 in combination with SQV. Geometric mean (coefficient of variation) ATV C(trough) was 110 ng/ml (2.38), 86 ng/ml (0.84) and 149 ng/ml (2.01) in groups 1, 2 and 3, respectively. ATV C(trough) in both double protease inhibitor combination regimens was not significantly different from that as a single protease inhibitor [geometric mean ratio (GMR): 0.77; 95% confidence interval (CI): 0.38-1.58, P=not significant for group 2 versus group 1 and 1.34, 0.40-4.49, P=not significant, for group 3 versus group 1). Patients treated with ATV plus APV had a 40.2% lower ATV C(max) and a 30.8% smaller ATV AUC than the reference group treated with unboosted ATV alone: both these differences were statistically significant (GMR, 95% CI: 0.59, 0.41-0.85, P=0.005 and 0.69, 0.48-0.99, P=0.056, respectively). No difference was observed for either C(max) or AUC between the group treated with ATV plus SQV and the reference group (GMR, 95% CI: 0.78, 0.47-1.30, P=not significant and 1.24, 0.73-2.10, P=not significant, respectively).


CONCLUSIONS
ATV pharmacokinetics does not seem to be influenced by the concomitant administration of SQV, whereas APV significantly lowers plasma ATV levels.
Seminari
Elena
E
Infectious Disease Department, San Raffaele Scientific Institute, Vita-Salute University, Via Stamira d'Ancona 20, 20122 Milan, Italy.
Guffanti
Monica
M
Villani
Paola
P
Gianotti
Nicola
N
Cusato
Maria
M
Fusetti
Giuliana
G
Galli
Andrea
A
Castagna
Antonella
A
Regazzi
Mario
M
Lazzarin
Adriano
A
D000328:Adult; D000069446:Atazanavir Sulfate; D002219:Carbamates; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D005260:Female; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010865:Pilot Projects; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; C095108:amprenavir; D019258:Saquinavir