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 Emax 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.

Population Pharmacokinetics of Lopinavir in Severely Malnourished HIV-infected Children and the Effect on Treatment Outcomes

“…In this pharmacokinetic evaluation of LPV, severely malnourished children displayed significant pharmacokinetic variability, reduced bioavailability and consequently greater CL/F estimate of 0.6 L/h/kg in comparison to reports from other studies in non-malnourished children of LPV CL/F ranging from 0.2 to 0.4 L/h/kg (15,22,23). The findings are in keeping with the results from a recently published study conducted in Ugandan children, where there was a trend towards lower LPV bioavailability in malnourished compared to non-malnourished children.…”

Factors Associated with the Development of Drug Resistance Mutations in HIV-1 Infected Children Failing Protease Inhibitor-Based Antiretroviral Therapy in South Africa

“…While LPV/R+ achieves acceptable LPV concentrations in >85% of children [ 67 , 68 ] it does not completely counteract rifampicin induction of lopinavir in very young children and has been complicated by concerns about significant hepatotoxicity in healthy adult volunteers [ 61 , 69 ]. Zhang et al [ 70 ] proposed that an 8-hourly dosing regimen with LPV/r might maintain therapeutic levels of LPV during TB treatment, but this strategy has not yet been assessed in clinical trials.…”

Simultaneous Population Pharmacokinetic Modelling of Atazanavir and Ritonavir in HIV-Infected Adults and Assessment of Different Dose Reduction Strategies

“…A 1-compartment model with first-order absorption and elimination with the presence of lag time described the PK of both ATV and RTV separately, which was consistent with previous studies. 10,15,24,25,27,28 Zhang et al 26 described a 2-compartment model for RTV, using a transit absorption model. We tried to incorporate the transit absorption, however, the model had problems converging, so was not included in the final combined model.…”