Background:  Lopinavir/ritonavir (LPV/r; Kaletra) is FDA-approved for use in children at a dose of 230 mg/M²/dose by mouth every 12 hours, and has been shown to be safe up to a dose of 300 mg/M²/dose by mouth every 12 hours in children. Safety of higher doses in children and adolescents has not been reported.

Methods:  In this retrospective observational study we examined patient records for LPV/r administered dose (mg/M²/dose), drug exposure (LPV plasma concentration 12 hours post-dose), and possible drug-related toxicity in pediatric and adolescent patients cared for in a single HIV clinic, and treated with more than 300 mg/M²/dose of LPV/r between August 1, 2001 and September 19, 2003. For patients with more than one measured LPV plasma concentration, only data obtained while on the highest administered dose were used for the analysis. Routine laboratory evaluation for possible drug-related toxicity was performed at least monthly for 3 months at the start of therapy, and every 3 months thereafter. LPV plasma concentration was measured by commercially available assays. 

Results:  Of 16 children and adolescents with perinatally acquired HIV infection treated with LPV/r, 12 (median age 10.3 years; range 1.7 to 17.6 years) were treated with doses higher than 300 mg/M²/dose by mouth every 12 hours (median dose 376 mg/M²/dose by mouth every 12 hours; range 319 to 467). Median LPV plasma concentration in these 12 patients was 8.7 mg/mL (range 3.9 to 16.9) measured at a median of 12.0 hours after an administered dose (range 11.5 to 13h). LPV plasma concentration was only weakly correlated with administered dose (r = 0.53, p = 0.08; figure) For 4 subjects treated concurrently without an NNRTI the median LPV/r dose was 401 mg/M²/dose by mouth every 12 hours (range 346 to 467), and the median LPV/r plasma concentration was 9.9 mg/mL (range 5.3 to 16.9). For 8 subjects treated concurrently with an NNRTI, the median LPV/r dose was 372 mg/M²/dose every 12 hours (range 319 to 454), and the median LPV/r plasma concentration was 8.5 mg/mL (3.9 to 16.0). During a median duration of therapy of 1.3 years (range 0.2 to 2.9) there were no patients with drug-related toxicity that required dose reduction or change in LPV therapy. 

Conclusions: These high doses of LPV/r are well tolerated in children and adolescents. The relationship between administered dose and plasma concentration demonstrates that within an individual subject, drug exposure cannot be predicted from administered dose.

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Keywords: Children; lopinavir; pharmacokinetics