Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children

Abstract

Background: The preferred antiretroviral regimen for young children previously exposed to non-nucleoside reverse transcriptase inhibitors is lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors. Rifampicin-based antitubercular treatment reduces lopinavir concentrations. Adding extra ritonavir to lopinavir/ritonavir overcomes the effect of rifampicin, however this approach is not feasible in many settings.

Methods: We developed an integrated population model describing lopinavir and ritonavir pharmacokinetics to predict lopinavir/ritonavir (4:1) doses achieving target lopinavir exposures in children treated for tuberculosis. The model included data from 15 children given 'super-boosted' lopinavir (lopinavir/ritonavir =1:1) and 20 children given twice the standard dose of lopinavir/ritonavir every 12 h during antitubercular treatment, and from children given standard lopinavir/ritonavir doses every 12 h (39 without tuberculosis and 11 sampled again after antitubercular treatment).

Results: A one-compartment model with first-order absorption and elimination best described the pharmacokinetics of lopinavir and a one-compartment model with transit absorption compartments described ritonavir pharmacokinetics. The dynamic influence of ritonavir concentration on lopinavir oral clearance was modelled as direct inhibition with an E(max) model. Antitubercular treatment reduced the oral bioavailability of lopinavir by 77% in children receiving twice usual lopinavir/ritonavir doses and increased ritonavir clearance by 50%. Simulations predicted that respective 27, 21, 20 and 18 mg/kg 8-hourly doses of lopinavir (in lopinavir/ritonavir, 4:1) maintains lopinavir concentrations >1 mg/l in at least 95% of children weighing 3-5.9, 6-9.9, 10-13.9 and 14-19.9 kg.

Conclusions: The model describing the interactions between lopinavir, ritonavir and rifampicin in young children predicted feasible 8-hourly doses of lopinavir/ritonavir resulting in therapeutic lopinavir concentrations during antitubercular treatment.

Figures

Figure 1

Structure of the final integrated LPV–RTV pharmacokinetic model A, amount of transit absorption compartment; C, concentration; CL/F, apparent oral clearance; EC50, the ritonavir (RTV) concentration needed to reach half of the maximum inhibition effect on lopinavir (LPV) oral clearance by RTV (Emax); ka, absorption rate constant; kTA, transit absorption rate constant; MIT, mean transit time; V, volume of distribution; V/F, apparent volume of distribution.

Figure 2

The influence of ritonavir concentrations on the oral clearance of lopinavir LPV CL, lopinavir clearance; RTV Cone, ritonavir concentration.

Figure 3

Visual predictive check of the final combined model for LPV and RTV stratified for regimen From left to right are shown: standard, ‘super-boosted’ and ‘double dose’ approaches. 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% Cls for the median, 5th percentile and the 95th percentiles of the simulated dilta (n=1,000), Observed concentrations are displayed as circles. LPV, lopinavir; RTV, ritonavir.

Figure 4

The 5th percentile of simulated LPV concentrations obtained for a typical patient using different dosage regimens The solid line is the target concentration of 1 mg/l. LPV, lopinavir.