Pharmacokinetics, food intake requirements and tolerability of once-daily combinations of nelfinavir and low-dose ritonavir in healthy volunteers

Abstract

Aims: This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir.

Methods: Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2,000/200 mg (group 1), 2,000/400 mg (group 2) or 2,500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively.

Results: Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC(24h) values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h Cmin concentrations of nelfinavir were 0.76 mg l(-1), 0.43 mg l(-1) and 0.47 mg l(-1), respectively. Co-administration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC(24h) and Cmin values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1,250 mg BID without ritonavir). In the 2,000/200 mg group, seven out of eight subjects had a Cmin value of nelfinavir plus M8 above a threshold of 1.0 mg l-1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC(24h) and Cmin of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined). Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%).

Conclusions: Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2,000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.

Figure 1

Nelfinavir steady-state plasma concentrations on day 15 (geometric mean values) after administration of once daily (OD) nelfinavir/ritonavir combinations. In-house reference data for nelfinavir 1250 mg BID are displayed for reference (see also Table 5). ○, 2000/200 mg OD; □, 2000/400 mg OD; ▵ 2500/200 mg OD, •, 1250 mg OD.

Figure 2

M8 steady-state plasma concentrations on day 15 (geometric mean values) after administration of once daily (OD) nelfinavir/ritonavir combinations. In-house reference data for M8 (after administration of nelfinavir 1250 mg) are displayed for reference (see also Table 5). ○, 2000/200 mg OD; □, 2000/400 mg OD; ▵ 2500/200 mg OD, •, 1250 mg OD.

Figure 3

Individual 24-h trough concentrations (C_min) for nelfinavir (left panel) or nelfinavir plus M8 (right panel). Group 1: nelfinavir/ritonavir 2000/200 mg once daily. Group 2: nelfinavir/ritonavir 2000/400 mg once daily. Group 3: nelfinavir/ritonavir 2500/200 mg once daily. Proposed threshold values for treatment-naive patients are depicted as dotted lines (see text): nelfinavir 0.45 mg l⁻¹ and 0.8 mg l⁻¹; nelfinavir plus M8 1.0 mg l⁻¹.