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

Abstract

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 drugs routinely used for MDR-TB treatment in HIV-infected children. A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 with MDR-TB receiving 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. 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 the ritonavir concentration on lopinavir clearance was described using a maximum inhibition model. Even after adjustment for the effect of body weight with allometric scaling, a large variability in lopinavir and ritonavir exposure, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir, was detected. 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 children with MDR-TB, 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was found to have no significant effect on the key pharmacokinetic parameters of lopinavir or ritonavir. These findings should be considered in the context of the large interpatient variability found in the present study and the study's modest sample size.

Keywords: Mycobacterium tuberculosis; antiretroviral agents; drug interactions; human immunodeficiency virus; multidrug resistance; pediatric drug therapy; pediatric infectious disease; pharmacokinetics; population pharmacokinetics.

FIG 1

Structure of the final integrated lopinavir-ritonavir pharmacokinetic model. Cmpt, compartment; LPV, lopinavir; RTV, ritonavir; CL, clearance; V, apparent volume of distribution; k_a, absorption rate constant; inhibition = (I_max · C_RTV^γ)/(EC₅₀^γ + C_RTV^γ), which describes the inhibitory effect of the concentration of ritonavir (C_RTV) on the clearance of lopinavir described with an I_max relationship, where I_max is the maximum inhibitory effect of the ritonavir concentration on lopinavir clearance, EC₅₀ is the concentration at which 50% of the maximal inhibitory effect is obtained, and γ, also known as the Hill coefficient, is the shape factor of the curve.

FIG 2

Visual predictive check of the combined pharmacokinetic model for lopinavir and ritonavir in HIV-infected children stratified by MDR-TB versus controls, using 1,000 simulations. The solid and dashed lines represent the 10th, 50th, and 90th percentiles of the observed data, while the shaded areas (pink and blue) are the model-predicted 90% confidence intervals for the same percentiles. Observed data are displayed as dots, with resimulated censored data points (points at the LLOQ) being indicated in red.

FIG 3

Dynamic influence of the ritonavir concentration on lopinavir clearance in a typical 11-kg child. The dots represent the range (minimum and maximum) over which the ritonavir concentrations were observed.

FIG 4

Model-based individual estimates of lopinavir morning trough concentrations (0 h) in HIV-infected children stratified by children with MDR-TB (cases) and children without MDR-TB (controls). These values were obtained on the basis of the model individual predictions (a posteriori mode).