Pharmacokinetics and drug-drug interactions of lopinavir/ritonavir administered with first and second-line antituberculosis drugs in HIV-infected children treated for multidrug-resistant tuberculosis [PublishAheadOfPrint]

Background Lopinavir/ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir/ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir/ritonavir and routine drugs used for MDR-TB treatment in HIV-infected children.

Methods A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 on MDR-TB treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin: and 16 without TB), who were established on a lopinavir/ritonavir-containing antiretroviral regimen.

Results One-compartment models with first-order absorption and elimination for both lopinavir and ritonavir were combined into an integrated model. The dynamic inhibitory effect of ritonavir concentration on lopinavir clearance was described using an Imax model. Even after adjusting for the effect of body weight with allometric scaling, large variability in lopinavir and ritonavir exposure was detected, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir. MDR-TB treatment did not have a significant effect on the bioavailability, clearance, or absorption rate constants of lopinavir or ritonavir. Most children (81% of MDR-TB; 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/L).

Conclusions No significant effect was found on key pharmacokinetic parameters of lopinavir or ritonavir when co-administered with routine drugs used for MDR-TB. These findings should be considered in the context of large inter-patient variability and the modest sample size.

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