AIDS. 1997 Mar 15;11(4):F29-33.  

Saquinavir pharmacokinetics alone and in combination with ritonavir in
HIV-infected patients.

Merry C, Barry MG, Mulcahy F, Ryan M, Heavey J, Tjia JF, Gibbons SE,
Breckenridge AM, Back DJ.

Department of Pharmacology and Therapeutics, University of Liverpool, UK.

OBJECTIVE: The most important hepatic enzyme involved in the metabolism of
protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent
inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy
volunteers. In this study we investigated the kinetics of SQV when administered
alone and in combination with RIT in HIV-infected patients. DESIGN: SQV
pharmacokinetics were determined in seven patients who had advanced HIV disease.
Steady-state SQV profiles were obtained on two occasions following treatment
with SQV 600 mg three times daily alone and when administered with RIT 300 mg
twice daily. METHODS: Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h
post-dosing. Following centrifugation, separated plasma was heated at 58 degrees
C for at least 30 min to inactivate HIV and stored at -80 degrees C until
analysis using high performance liquid chromatography. RESULTS: For patients
treated with SQV alone there was a 12-fold variability in the area under the SQV
concentration-time curve (AUC0-8h) ranging from 293 to 3446 ng.h/ml. When
combined with RIT there was a marked increase in the maximum plasma
concentration of SQV [median (range), 146 (57-702) versus 4795 (1420-15810)
ng/ml; approximately 95% confidence interval (CI), 2988-6819; P = 0.0006,
Mann-Whitney U test]. The AUC0-8h for SQV was also significantly increased in
the presence of RIT [median (range), 470 (29-3446) versus 27,458 (7357-108,001)
ng.h/ml; approximately 95% CI, 16,628-35,111; P = 0.0006]. CONCLUSIONS: For some
patients, administration of SQV 600 mg three times daily results in very low SQV
plasma levels and possibly little antiviral effect. Combination of SQV with RIT
results in a significant drug interaction mediated by enzyme inhibition which
exposes patients to very high SQV concentrations and potential toxicity