Chao Zhang1, Paolo Denti1, Eric Decloedt1, Yuan Ren1, Mats O Karlsson2, Helen McIlleron1*
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.2Department of Pharmaceutical Biosciences,Uppsala University, Uppsala, Sweden.
Objectives: Doubling the dose of lopinavir/ritonavir has been shown to compensate for the induction effect of rifampicin in adults, but fails to result in adequate concentrations in most young children [1]. The objective of this study was to develop a population pharmacokinetic model to investigate the pharmacokinetic differences between children and adults in the drug-drug interactions between lopinavir, ritonavir and rifampicin.
Methods: The data from three previously published pharmacokinetic studies were combined. Lopinavir and ritonavir concentrations were included from: 21 HIV-infected adults established on standard twice daily doses of lopinavir/ritonavir which were escalated up to 2-fold after the introduction of rifampicin; 35 HIV-infected children with tuberculosis were given adjusted lopinavir/ritonavir dose co-administration with rifampicin; and 39 HIV-infected children without tuberculosis given standard lopinavir/ritonavir doses. An integrated population pharmacokinetic model describing lopinavir and ritonavir pharmacokinetics in adults and children with and without concomitant rifampicin was developed using NONMEM 7.
Results: Rifampicin reduced the bioavailability of lopinavir by 72.8%in children (an effect that was moderated by the dose of ritonavir) and 20.6% in adults.The bioavailability of ritonavir was decreased by 72.2% and 48.2% in the presence of rifampicin, in children and adults respectively. Hence, compared to adults, the relative bioavailability of lopinavir and ritonavir in children was 89% and 11.8% respectively for a 1.8 mg/kgritonavir dose. Conversely, rifampicin increased the oral clearance of both lopinavir and ritonavir to a lesser extentin children than in adults. In children, the absorption rate of lopinavir was reduced, and the mean transit time of ritonavir was lengthened, compared to those in adults.
Conclusions: The model described substantially different effects of rifampicin on the bioavailability and oral clearance of lopinavir and ritonavir between adults and children. Hence, such drug-drug interactions should be evaluated in children as adult studies cannot be relied on to predict the magnitude of paediatric drug-drug interactions.
References:
[1] H. McIlleron et al., "Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis.," Antiviral therapy, vol. 16, no. 3, pp. 417-21, Jan. 2011.
Reference: PAGE 21 () Abstr 2400 [www.page-meeting.org/?abstract=2400]
Poster: Infection