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

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.