Population Pharmacokinetics of Lopinavir and Ritonavir in Combination with Rifampicin-based Antitubercular Treatment in HIV-infected Adults
Chao Zhang1, Eric Decloedt1, Paolo Denti1, Ulrika SH Simonsson2, Mats O.Karlsson2, Gary Maartens1, Helen McIlleron1
1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; 2 Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Objectives: Lopinavir is an antiretroviral drug administered with ritonavir to enhance its exposure. Rifampicin, a key component of antitubercular treatment, profoundly reduces lopinavir concentrations. Increasing the amount of fixed dose combination of lopinavir/ritonavir (4:1, LPV/r) has been shown to overcome this effect. The aim of this study was to develop an integrated population pharmacokinetic model accounting for all the drug-drug interactions between lopinavir, ritonavir and rifampicin, and to evaluate optimal dose of LPV/r when coadministered with rifampicin.
Methods: Steady state pharmacokinetics of lopinavir and ritonavir were evaluated at baseline in a cohort of 21 HIV-infected South African adults virologically suppressed on a LPV/r regimen (400 mg/100 mg 12 hourly). Rifampicin 600mg daily was then introduced. After one week of rifampicin, the LPV/r dose was increased 1.5 times (600 mg/150 mg 12 hourly), and after another week it was doubled (800 mg/200 mg 12 hourly). Intensive pharmacokinetic sampling was performed one week after each dose adjustment following a morning dose, administered on an empty stomach. A population pharmacokinetic analysis was conducted using NONMEM VII.
Results: A simultaneous integrated model was built in this study. A one-compartment model with first-order absorption and elimination best described the pharmacokinetics of lopinavir, while a two-compartment model with transit compartments was used for ritonavir. Rifampicin reduced the oral bioavailability of lopinavir and ritonavir by 68.2% and 59.1% respectively, and it increased their clearance by 68.0% and 33.8% respectively. With increasing concentrations of ritonavir, clearance of lopinavir decreased in an Emax relationship. Exposure to ritonavir increased by 48.2% for every 100 mg increment in its dose. Morning trough concentrations of lopinavir were on average higher than the evening trough concentrations, although the trend was not consistent in all subjects or occasions. Simulation indicated that, keeping the same pharmacokinetic parameters, the dose of LPV/r would need to be increased 2.7 times to account for the difference.
Conclusions: The model describes the drug-drug interactions between lopinavir, ritonavir and rifampicin. Doubling the dose of LPV/r seems to counteract the effect of rifampicin in most patients. The difference between morning and evening trough concentrations is unlikely to be entirely explained by increased absorption with the evening meal.
 La Porte CJL, Colberes EPH, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampicin in healthy volunteers. Antimicrob Agents Chemother. 2004;48:1553-1560.
 W.Awnl, Y.L.Chlu, T. Zhu, et al. Significantly reduced food effect and pharmacokinetic variability with a novel lopinavir/ritonavir tablet formulation. Third IAS conference on HIV pathogenesis and treatment. 24-27 July, 2005, Rio de Janeiro, Brazil.