Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band-based dosing

Abstract

Improved antiretroviral therapies are needed for the treatment of HIV-infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV-infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.

Figure 1

Goodness of fit plots. LPV concentrations (intensive and sparse PK data) from the study were compared with: A. Individual predictions for LPV levels and B. Population PK predicted LPV levels.

Figure 2

Population PK model results. Estimated lopinavir apparent clearance (CL/F) versus age. The post-hoc empiric Bayesian estimated CL/F was derived from the final pharmacokinetic model for intensive and sparse PK visits. The solid line represents the population based apparent clearance profile which was derived using the allometrically scaled median weight for each age group (WHO 50^th percentile weight). Cross-validation of the final model demonstrated a median absolute error similar to the residual error of the model, (50%, 25% to 112%, 25th–75th percentile). There was positive bias in the model with a median error of 18% (–29% to 112%, 25th-75th percentile) likely due to some non-adherence before sparse sample collections.

Figure 3

Monte Carlo simulations using the FDA dose (300 mg/m², <6 months of age; 230 mg/m² >6 months of age), study dose (300 mg/m²), and WHO weight band dosing recommendations. Median and interquartile range (IQR) of WHO weight band dosing (mg/m²): 0.5-2 months: 377.3 (337.4 – 421.8), 3-6 months: 309.4 (285.9 – 366.7), >6 months: 286.6 (262.7 – 306.7). A. Median LPV trough concentrations (C12). Data represent the median and inter-quartile range of LPV trough concentrations. Median adult trough level is presented by dashed line (4.2 μg/mL). B. Predicted frequency of very low LPV troughs (<1 μg/mL). C. Median drug exposure (area under the curve). Data represent the median and interquartile range of LPV AUC (μg*hr/mL). Mean adult AUC level is presented by dashed line (82.8 μg*hr/mL).