Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria

Abstract

Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin-piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. Young children (2-5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated.

Figure 1

Final structural model for piperaquine population pharmacokinetics in children with uncomplicated falciparum malaria in Burkina Faso. CL, elimination clearance; F, relative oral bioavailability; ktr, transit absorption rate constant; Q, intercompartment clearance; V_C, apparent volume of distribution of the central compartment; V_P, apparent volume of distribution of the peripheral compartment.

Figure 2

Goodness-of-fit diagnostics of the final population pharmacokinetics model of piperaquine in children with uncomplicated falciparum malaria in Burkina Faso. Open circles: observed data points; broken line: a locally weighted least-squares regression; solid line: line of identity. The observed capillary plasma piperaquine concentrations, population predictions, and individual predictions were transformed into their logarithms (base 10).

Figure 3

Prediction-corrected visual predictive check of the final model describing the population pharmacokinetics of piperaquine in children with uncomplicated falciparum malaria in Burkina Faso. Open circles: observed data points; solid lines: 5th, 50th, and 95th percentiles of the observed data; shaded area, 95% confidence interval of simulated (n = 2,000) 5th, 50th, and 95th percentiles. Capillary plasma piperaquine concentrations were transformed into their logarithms (base 10).

Figure 4

Observed and simulated day 7 capillary piperaquine concentrations stratified for body weight (1,000 simulated patients at each body weight) after different dose regimens. Black circles: median values ± interquartile range; black solid horizontal line: cutoff value for therapeutic failure (57 ng/ml for capillary concentrations). (a) Observed day 7 capillary concentrations; (b) predicted day 7 capillary concentrations after the dose regimen used in this study; (c) predicted day 7 capillary concentrations after the dose regimen proposed by Sigma-tau; (d) predicted day 7 capillary concentrations after an increased dose regimen to achieve >75% of concentrations above the defined cutoff at each body weight (Table 3).