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

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

The pharmacokinetics of combination therapy with nelfinavir plus nevirapine.

OBJECTIVE: To investigate the pharmacokinetics of nelfinavir (NFV) administered alone and in combination with nevirapine (NVP) to HIV-positive patients. DESIGN: Seven patients with advanced HIV disease received dual nucleoside analogues in addition to NFV (750 mg three times daily) and subsequently NVP (200 mg daily for 2 weeks followed by 200 mg twice daily) as salvage therapy. On the first study day (day 3), blood samples were taken for assay of NFV. The second study day followed the introduction of NVP for 3 weeks. METHODS: Blood samples were obtained at 0, 1, 2, 3, 4, 6 and 8 h after dosing on both study days. Separated plasma was heated to 58 degrees C for 30 min to inactivate HIV and stored at -80 degrees C until analysis by high performance liquid chromatography for both NFV and NVP. RESULTS: The geometric mean NFV area under the concentration-time curve to 8 h (AUC0-8h) was 23.4 microg x h/ml (range, 13.5-49.2) and 11.6 microg x h/ml (range, 6.6-23.2) on the first and second study days, respectively. The geometric mean ratio was 0.49 (95% confidence interval, 0.33-0.72; P = 0.016). This represented a 50% reduction in plasma NFV concentrations. Maximum and minimum concentrations were also reduced during NVP therapy (from 4.4 to 2.5 microg/ml and from 1.7 to 0.8 microg/ml, respectively). Time to maximum concentration was reduced from 4 to 2 h. NVP concentrations were determined with a maximum concentration of 5.4 microg/ml at 4 h. CONCLUSIONS: NVP is currently being used in combination therapy with protease inhibitors for antiretroviral-experienced patients in the setting of treatment failure. This study demonstrates that when patients are coadministered NVP there is a 50% reduction in the plasma AUC of NFV. Although the mean trough concentrations of NFV remained above the stated minimum effective concentration of 0.4 microg/ml, there is nevertheless concern that some patients will fall below this value when NVP is added to treatment regimens. In the absence of therapeutic drug monitoring we suggest that an increase in the standard NFV dosage of 750 mg three times daily will be required to ensure satisfactory NFV plasma concentrations, thereby maintaining antiviral efficacy.