Population Pharmacokinetics of Lopinavir/Ritonavir in Combination with Rifampicin-based Antitubercular Treatment in HIV-infected Children
Chao Zhang1, Paolo Denti1, Jan-Stefan van der Walt1,2, Ulrika SH Simonsson2, Gary Maartens1, Mats O.Karlsson2, 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: Children with HIV associated tuberculosis often require coformulated lopinavir/ ritonavir (LPV/RTV)-based antiretroviral treatment with rifampicin-based antitubercular treatment (ATT). Rifampicin (RIF), a potent inducer of drug-metabolizing systems, profoundly reduces the bioavailability of LPV. The aims of this study were to develop an integrated population pharmacokinetic (PK) model describing LPV and RTV PK in children with and without concomitant ATT using two different dosing approaches and to estimate doses of LPV/RTV achieving target exposures during ATT in young children.
Methods: A population PK analysis was conducted in NONMEM. During ATT 15 children were given LPV with extra RTV (LPV/RTV ratio 1:1) and 20 children were given twice the usual dose of LPV/RTV (ratio 4:1) 12 hourly; 39 children without tuberculosis and 11 children undergoing repeated sampling after ATT were treated with standard 12 hourly doses of LPV/RTV (median LPV dose 11.6 mg/kg). Goodness-of-fit plots and visual predictive checks were used to evaluate the models.
Results: In a one-compartment model with first-order absorption to describe LPV PK, and a one-compartment model with transit absorption for RTV, the dynamic influence of RTV concentration on the clearance of LPV was modeled as direct inhibition with an Emax model. Allometric scaling for weight was used for clearance and volume of both LPV and RTV. During ATT, the relative oral bioavailability of LPV was reduced by 79% in children receiving twice the usual dose of LPV/RTV. The clearance of RTV was 19 L/h with, and 12.7 L/h without, ATT.The baseline clearance of LPV, when RTV was undetected, estimated 4.27 L/h. With increasing concentrations of RTV, clearance of LPV decreased in a sigmoid relationship (EC50 0.0497 mg/L). Volume of distribution for LPV and RTV were 11.7 and 105 L, respectively. Simulations predicted that children weighing 4-5.9, 6-7.9, 8-11.9 and 12-18 kg need respective doses of 65, 50, 40 and 35 mg/kg LPV/RTV (4:1) 12 hourly in order to maintain LPV concentrations > 1 mg/L in at least 5% of children.
Conclusions: The model describes the drug-drug interaction between LPV, RTV and RIF. Using 12 hourly doses, approximately 2.5 to 5.5 times the standard doses are required to maintain therapeutic LPV concentrations in young children during ATT.
References:
[1] 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.
[2] Natella R, John van den A, Aline B, et al. Population pharmacokinetics of lopinavir predict suboptimal therapeutic concentrations in treatment-experienced human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2009; 53:2532-2538.
