Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children

Objective: To assess the pharmacokinetics and 24-week efficacy and safety of dual boosted saquinavir/lopinavir/ritonavir combination in children. Design: Twenty reverse transcription inhibitor-pretreated children at 2 centers in Thailand were treated with saquinavir/lopinavir/ritonavir in an open label, single arm, 6-month prospective study. The dosage was 50 mg/kg twice daily (bid) for saquinavir and 230/57.5 mg/m(2) bid for lopinavir/ritonavir. Ten children also received lamivudine. Methods: Samples were collected for a 12-hour pharmacokinetic profile in all children. Plasma concentrations of saquinavir, lopinavir and ritonavir were determined using a validated high performance liquid chromatography technique. Results: At baseline, the median age was 8.5 years, with human immunodeficiency virus (HIV) RNA 4.9 log(10) copies/mL, CD4 count 129 cells/mu L and CD4%, 6.5%. Median area under the concentration curve at 0-12 hours and C-min were 39.4 mg/L (.) h and 1.4 mg/L for saquinavir and 118 mg/L (.) hr and 5.9 mg/L for lopinavir. After 24 weeks of treatment, HIV RNA was suppressed below 400 copies/mL for 16 of 20 (80%) children (intent-to-treat analysis) and below 50 copies/mL for 12 of 20 children (60%), and CD4% (count) rose by a median of 6% (216 cells/mu L). Median changes of triglyceride and total cholesterol were 56 and 36.5 mg/dL, respectively (P = 0.01). Lopinavir C-min < 1 and saquinavir C-min < 0.28 mg/L correlated with HIV RNA > 400 copies/mL, and lopinavir C-max > 15 mg/L correlated with rises in cholesterol (P < 0.05). Conclusion: Plasma drug concentrations of saquinavir, lopinavir and ritonavir were at the higher limits of expected ranges for adult treatment at approved dosages (1000/100 mg bid for saquinavir, 400/100 mg bid for lopinavir/ritonavir). The regimen was well-tolerated and had good efficacy at 24 weeks. This dual boosted protease inhibitor combination should be assessed in larger trials of reverse transcription inhibitor-experienced children.