Pharmacokinetics of plasma lopinavir/ritonavir following the administration of 400/100 mg, 200/150 mg and 200/50 mg twice daily in HIV-negative volunteers

Abstract

Objectives: Data suggest that some licensed antiretroviral doses could be reduced. We assessed the safety, tolerability and pharmacokinetics of lopinavir/ritonavir at doses of 400/100, 200/150 and 200/50 mg twice daily in HIV-negative volunteers (https://ichgcp.net/clinical-trials-registry/NCT00985543).

Methods: Male and female volunteers were administered lopinavir/ritonavir at doses of 400/100 mg (two lopinavir/ritonavir Meltrex 200/50 mg tablets, Regimen 1), 200/150 mg (one Meltrex tablet, one 100 mg ritonavir capsule, Regimen 2) and 200/50 mg (one Meltrex tablet, Regimen 3). Each dose was given twice daily for 7 days sequentially, separated by a 7 day wash-out period. Lopinavir/ritonavir steady-state pharmacokinetics was assessed over 12 h at the end of each phase (days 7, 21 and 35). Pharmacokinetic parameters were compared using the 400/100 mg twice daily dose as reference, by determining geometric mean ratios (GMRs) and 90% confidence intervals.

Results: Twenty-two subjects (eight females) completed the study. Lopinavir AUC(0-12) (ng h/mL), C(max) (ng/mL) and the minimum concentration (C(trough)) (ng/mL) for the 400/100, 200/150 and 200/50 mg twice daily doses, respectively, were as follows: 99,599, 73,603 and 45,146; 11,965, 8939 and 6404; and 5776, 4293 and 1749. Lopinavir pharmacokinetic parameters were significantly lower for Regimens 2 and 3: GMR (90% CI) AUC(0-12), 0.74 (0.65-0.84) and 0.45 (0.40-0.51); C(max), 0.75 (0.66-0.85) and 0.54 (0.40-0.60); and C(trough), 0.74 (0.62-0.89) and 0.30 (0.25-0.36), respectively. All subjects taking the 400/100 and 200/150 mg twice daily doses, and 19 (86%) subjects taking 200/50 mg twice daily had lopinavir concentrations above the suggested minimum effective concentration of 1000 ng/mL.

Conclusions: These pharmacokinetic data show that therapeutic plasma concentrations of lopinavir can be achieved with 200/150 mg of lopinavir/ritonavir twice daily (one Meltrex tablet and one 100 mg ritonavir capsule twice daily).

Figures

Figure 1

Steady-state lopinavir plasma concentrations illustrated as GMs and 90% CIs measured during the intake of the three different regimens: 400/100 mg of lopinavir/ritonavir twice daily (diamonds); 200/150 mg of lopinavir/ritonavir twice daily (triangles); and 200/50 mg of lopinavir/ritonavir twice daily (circles).

Figure 2

Steady-state ritonavir plasma concentrations illustrated as GMs and 90% CIs measured during the intake of the three different regimens: 400/100 mg of lopinavir/ritonavir twice daily (diamonds); 200/150 mg of lopinavir/ritonavir twice daily (triangles); and 200/50 mg of lopinavir/ritonavir twice daily (circles).