Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin

Abstract

Aims: Rifampicin profoundly reduces lopinavir concentrations. Doubled doses of lopinavir/ritonavir compensate for the effect of rifampicin in adults, but fail to provide adequate lopinavir concentrations in young children on rifampicin-based antituberculosis therapy. The objective of this study was to develop a population pharmacokinetic model describing the pharmacokinetic differences of lopinavir and ritonavir, with and without rifampicin, between children and adults.

Methods: An integrated population pharmacokinetic model developed in nonmem 7 was used to describe the pharmacokinetics of lopinavir and ritonavir in 21 HIV infected adults, 39 HIV infected children and 35 HIV infected children with tuberculosis, who were established on lopinavir/ritonavir-based antiretroviral therapy with and without rifampicin-containing antituberculosis therapy.

Results: The bioavailability of lopinavir was reduced by 25% in adults whereas children on antituberculosis treatment experienced a 59% reduction, an effect that was moderated by the dose of ritonavir. Conversely, rifampicin increased oral clearance of both lopinavir and ritonavir to a lesser extent in children than in adults. Rifampicin therapy in administered doses increased CL of lopinavir by 58% in adults and 48% in children, and CL of ritonavir by 34% and 22% for adults and children, respectively. In children, the absorption half-life of lopinavir and the mean transit time of ritonavir were lengthened, compared with those in adults.

Conclusions: The model characterized important differences between adults and children in the effect of rifampicin on the pharmacokinetics of lopinavir and ritonavir. As adult studies cannot reliably predict their magnitude in children, drug-drug interactions should be evaluated in paediatric patient populations.

Keywords: adults; children; lopinavir/ritonavir; nonmem; population pharmacokinetics; rifampicin.

© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Figures

Figure 1

Structure of the final integrated lopinavir-ritonavir pharmacokinetic model. LPV, lopinavir; RTV, ritonavir; MTT, mean transit time; CL/F, apparent oral clearance; V/F, apparent volume of distribution; ka, absorption rate constant; kTR, transit absorption rate constant; Emax, the maximum inhibition effect on lopinavir oral clearance by ritonavir; EC50, the ritonavir concentration needed to reach half of Emax; C, concentration; hill, shape factor

Figure 2

The individual estimates of exposure for lopinavir (A) and ritonavir (B) for adults () and children () stratified by dose strategy. The values were obtained based on the model individual predictions for the observed dosing regimen when available, or on simulation for the unobserved dosing regimens (n = 21 for adult on all regimens; for children, n = 39 for standard dose with and without rifampicin, n = 15 for superboosted dose and n = 20 for double dose; log scale is used)

Figure 3

The individual estimates of C12 h trough concentration of lopinavir for adults () and children () stratified by dose strategy. The values were obtained based on the model individual predictions for the observed dosing regimen when available, or on simulation for the unobserved dosing regimens (log scale is used)

Figure 4

Visual predictive check of the final combined model for lopinavir (A) and ritonavir (B) in adults stratified by rifampicin from 1000 simulations. The solid line is the median of the observed data and the dotted lines are the 5th and 95th percentiles of the observed data. The grey shaded areas are the 95% confidence intervals for the median, 5th percentile and the 95th percentiles of the simulated data. Observed concentrations are displayed as circles

Figure 5

Visual predictive check of the final combined model for lopinavir (A) and ritonavir (B) in children stratified by dose strategy from 1000 simulations. The solid line is the median of the observed data and the dotted lines are the 5th and 95th percentiles of the observed data. The grey shaded areas are the 95% confidence intervals for the median, 5th percentile and the 95th percentiles of the simulated data. Observed concentrations are displayed as circles