Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV-infected patients

To investigate the pharmacokinetics of saquinavir (SQV) hard gel when administered alone and in combination with nelfinavir (NLF) to HIV-positive patients.

Six patients receiving triple therapy (dual nucleoside plus SQV 600 mg three times daily) were studied. On the first study day blood samples were drawn for assay of SQV. Prior to the second study day, patients received their usual medication plus NLF 750 mg three times daily for 2 days.

Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h after dosing on study days 1 and 2. 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.

The geometric mean Cmax and AUC0-8 h on the first study day were 253 ng/ml (range, < 25-1200 ng/ml) and 1106 ng/ml.h (range, < 100-3479 ng/ml.h), respectively, and on the second study day were 1204 ng/ml (range, 379-2755 ng/ml) and 5472 ng/ml.h (range, 1434-12,538 ng/ml.h), respectively. The geometric mean ratio for Cmax was 4.75 and for AUC0-8 h was 4.94.

NLF increases the oral bioavailability of SQV (hard gel) approximately fivefold. For some patients the addition of NLF to SQV will increase the drug levels from subtherapeutic to the therapeutic range. In one of our patients the addition of NLF resulted in SQV levels that were much higher than previous work suggests are necessary for maximum antiviral effect. The variability in SQV concentrations both at baseline and following addition of NLF suggest that dosing may best be adjusted by individual therapeutic drug monitoring.