Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients

Abstract

Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day(-1), respectively. Covariate model building conducted using forward addition (P < 0.05) followed by backward elimination (P < 0.001) yielded two significant covariate-parameter relationships, i.e., age on V2/F and formulation on Ka. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and NCT00541385, NCT00403260, NCT00422084, and NCT00440999 [phase III studies]. The most recent phase III study was registered at pactr.org under registration no. PACTR201105000286876.).

Copyright © 2016 Ayyoub et al.

Figures

FIG 1

Goodness of fit plots of pyronaridine for the final model. The solid lines in the top panels are lines of identity. The broken lines are smoothing lines.

FIG 2

Visual predictive check of the final model. The diamonds represent the observed concentrations, the dashed red lines represent the 5th and 95th percentiles, and the solid red line represents the 50th percentile obtained from the simulations. The shaded areas and corresponding dashed lines represent the simulated data prediction intervals about the observed data percentiles.

FIG 3

Distribution of interindividual variability for pyronaridine clearance from the central compartment (CL/F) (ETA1), volume of the central compartment (V2/F) (ETA2), intercompartmental clearance (Q/F) (ETA3), volume of the peripheral compartment (V3/F) (ETA4), and absorption rate constant (Ka) (ETA5) for the final model.

FIG 4

Fiftieth percentile simulated pyronaridine concentrations for a 5-kg, 6-month-old patient and a 7-kg, 6-month-old patient administered 1 sachet, an 8-kg, 7-month-old patient and a 14-kg, 3-year-old patient administered 2 sachets, and a 15-kg, 3-year-old patient and a 19-kg, 5-year-old patient administered 3 sachets.

FIG 5

Simulated pyronaridine AUC0–∞ (mg · day/liter) versus weight (kg) for malaria-infected subjects after the administration of the tablet dosage form for those weighing ≥20 kg and the granule dosage form for those weighing <20 kg.