Lopinavir/ritonavir population pharmacokinetics in neonates and infants

Abstract

What is already known about this subject: • Lopinavir/ritonavir pharmacokinetics have been fully investigated in adults and children.

What this study adds: • Lopinavir/ritonavir population pharmacokinetics in 96 neonates and infants from birth to less than 2 years (1.16 to 10.4 kg) showed that CL/F and V/F were dependent on body weight on an allometric basis and post-menstrual age.

Aims: Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

Methods: Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach. RESULTS A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87|h(-1) 70 kg(-1) and 91.7|70 kg(-1). The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

Conclusions: Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h(-1), 80 mg 12 h(-1) and 120 mg 12 h(-1) in the 1-2 kg, 2-6 kg and 6-10 kg group, respectively.

© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Figures

Figure 1

Diagnostic plots for the final population pharmacokinetic model: Observed LPV/r concentrations (DV) vs. model-predicted concentrations PRED in mg l−1 and the corresponding normalized prediction distribution errors (npde) metrics vs. predictions or vs. time after dose, along with the normal quantile–quantile plot for npde. The dotted lines join the data from same individuals. The lines indicate the lines of unity (left, middle) and the y = 0 line (right). npde statistics, mean and variance were not significantly different from zero (Wilcoxon signed rank test, P = 0.92) and 1 (Fisher variance test, P = 0.74) and the distribution was not significantly different from a normal distribution (Shapiro-Wilk test of normality, P = 0.52)

Figure 2

Probability of observing trough lopinavir concentrations, Ctrough in the therapeutic range, between 1–8 mg l−1 (solid lines), below 1 mg l−1 (dashed lines) or above 8 mg l−1 (toxic range, dotted lines) following administration of 20 to 160 mg 12 h−1 LPV/r in paediatric patients weighing from 1 to 10 kg. Predicted trough lopinavir concentrations were obtained from 500 Monte Carlo simulations of the final model for each dosage