Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen.
OBJECTIVE
To determine the pharmacokinetics of saquinavir hard-gel capsules/ritonavir/atazanavir co-administered once daily at 1600/100/300 mg in HIV-infected individuals.


METHODS
Eighteen patients receiving saquinavir/ritonavir switched to 1600/100 mg once daily a minimum of 3 days before the study. On study day 1, levels of saquinavir and ritonavir were determined over 24 h. Atazanavir (300 mg once daily) was then added to the regimen. On day 11, a pharmacokinetic analysis was performed. Atazanavir was discontinued on day 32. Drug concentrations were measured by high-pressure liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir and ritonavir pharmacokinetic parameters, with and without atazanavir. A safety analysis was performed at screening, days 1, 11, 32 and follow-up.


RESULTS
After the addition of atazanavir, statistically significant increases in saquinavir trough plasma concentration (Ctrough GMR, 95% CI 2.12, 1.72-3.50), maximum plasma concentration (Cmax 1.42, 1.24-1.94), area under the plasma concentration-time curve from 0-24 h (AUC0-24 1.60, 1.35-2.43) and ritonavir Cmax (1.58, 1.32-2.08), AUC0-24 (1.41, 1.22-1.74) were observed. The pharmacokinetics of atazanavir compared with those obtained in patients receiving atazanavir/ritonavir without saquinavir. Four patients developed scleral icterus and two jaundice. Total and unconjugated bilirubin increased approximately fivefold during atazanavir therapy.


CONCLUSIONS
The addition of atazanavir to saquinavir/ritonavir increased saquinavir Ctrough, Cmax and AUC0-24 by 112, 42 and 60%. Ritonavir Cmax and AUCo-24 increased by 34 and 41%. The regimen was well tolerated, with no significant change in laboratory parameters, except for the occurrence of hyperbilirubinemia.
Boffito
Marta
M
Chelsea and Westminster Hospital, London, UK. marta.boffito@chelwest.nhs.uk
Kurowski
Michael
M
Kruse
Guido
G
Hill
Andrew
A
Benzie
Andrew A
AA
Nelson
Mark R
MR
Moyle
Graeme J
GJ
Gazzard
Brian G
BG
Pozniak
Anton L
AL
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005782:Gels; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D011446:Prospective Studies; D011725:Pyridines / Q000627:therapeutic use*; D019438:Ritonavir / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019258:Saquinavir / Q000493:pharmacokinetics / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D005782:Gels; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019258:Saquinavir; D019438:Ritonavir