Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin
Rifampicin profoundly reduces lopinavir concentrations. Doubled doses of lopinavir/ritonavir compensate for the effect of rifampicin in adults, but fail to provide adequate lopinavir concentrations in young children on rifampicin-based antituberculosis therapy. The objective of this study was to develop a population pharmacokinetic model describing the pharmacokinetic differences of lopinavir and ritonavir, with and without rifampicin, between children and adults.
An integrated population pharmacokinetic model developed in nonmem 7 was used to describe the pharmacokinetics of lopinavir and ritonavir in 21 HIV infected adults, 39 HIV infected children and 35 HIV infected children with tuberculosis, who were established on lopinavir/ritonavir-based antiretroviral therapy with and without rifampicin-containing antituberculosis therapy.
The bioavailability of lopinavir was reduced by 25% in adults whereas children on antituberculosis treatment experienced a 59% reduction, an effect that was moderated by the dose of ritonavir. Conversely, rifampicin increased oral clearance of both lopinavir and ritonavir to a lesser extent in children than in adults. Rifampicin therapy in administered doses increased CL of lopinavir by 58% in adults and 48% in children, and CL of ritonavir by 34% and 22% for adults and children, respectively. In children, the absorption half-life of lopinavir and the mean transit time of ritonavir were lengthened, compared with those in adults.
The model characterized important differences between adults and children in the effect of rifampicin on the pharmacokinetics of lopinavir and ritonavir. As adult studies cannot reliably predict their magnitude in children, drug–drug interactions should be evaluated in paediatric patient populations.