Pharmacokinetics of lopinavir/ritonavir in infants less than 12 months of age

A paper published in the January 11 edition of AIDS reported findings from an evaluation of the pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r)-based treatment in HIV-positive infants 6 weeks to 6 months of age. This multicentre trial was conducted by the Pediatric AIDS Clinical Trials Group (PATCG) in the United States and Brazil . The study is a prospective, open label, phase I/II trial with planned 48 week follow up. These findings were from an interim evaluation at 24 weeks.

21 infants with a median age of 14.7 weeks (range 6.9-25.7) were enrolled; 19 infants completed >/= 24 weeks of the study. The infants received LPV/r 300/75 mg/m2 twice daily plus two nucleoside reverse transcriptase inhibitors.

At week 2, a 12-hour intensive pharmacokinetic study was performed. If the trough LPV concentration (Ctrough) was < 1 ug/ml in an infant whose adherence was considered to be adequate, the LPV/r dose was increased to 450/112.5 mg/m2, twice-daily. If the lopinavir area under the concentration-time curve 0-12 h (AUC 0-12) was > 170 ug.h/ml, the LPV/r dose was reduced to 230/57.5 mg/m2, twice-daily.

If an infant required dose adjustments, a repeat pharmacokinetic study was performed 2 weeks following the change of dose.

The investigators reported that although LPV/r apparent clearance was slightly higher than found in older children, the median area under the concentration-time curve 0-12 hours (67.5 ug.h/mL) was in the range reported from older children taking the recommended dose of 230/57.5 mg/m2.

One infant in this study fulfilled the criteria for dose increase based on the pharmacokinetic evaluation at week 2. The repeat pharmacokinetic study with the increased dose showed LPV concentrations in the acceptable range.

Predose concentrations stabilised at a higher level after the first 2 weeks of the study. At week 24, 53% of the infants (10/19) had viral load < 400 copies/mL, and a median decrease of -3.33 log copies/mL, (95% CI, 1.71-3.46). The investigators suggested that poor adherence contributed to delayed viral load suppression, but this improved with improved with longer follow-up.

Three infants (14%) in the study had adverse events of grade 3 or more that were possibly related to study treatment but these were transient and did not require treatment discontinuation.

The investigators concluded: Despite the higher clearance of LPV/r in young infants, a twice daily dose of 300/75 mg/m2 LPV/r provides similar exposure to that seen in older children, albeit slightly less than seen in adults. Furthermore, LPV/r appears to provide favorable virological and clinical efficacy in this age range even when virological decay is prolonged.

Chadwick EG; Capparelli EV; Yogev, R et al. Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS: Volume 22(2)11 January 2008 p 249-255.