Piperaquine Pharmacokinetics during Intermittent Preventive Treatment for Malaria in Pregnancy

Abstract

Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4- to 8-week intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, at the time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modeling with a prior approach. In total, data from 366 Kenyan and 101 Indonesian women were analyzed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n = 5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% confidence interval [CI], 1.8 to 26.5%) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/ml). Translational simulations suggest that providing the full treatment course of DP at monthly intervals provides sufficient protection to prevent malaria infection. Monthly administration of DP has the potential to offer optimal prevention of malaria during pregnancy. (This study has been registered at ClinicalTrials.gov under identifier NCT01669941 and in the ISRCTN under number ISRCTN34010937.).

Keywords: dihydroartemisinin-piperaquine; intermittent preventive treatment in pregnancy; nonlinear mixed-effects modeling; population pharmacokinetic model.

FIG 1

Goodness of fit of piperaquine, stratified by study sites. (A) Population predictions versus observations; (B) individual predictions versus observations; (C) population predictions versus conditionally weighted residual errors; (D) distribution of the normalized prediction distribution errors. Open circles are venous plasma concentrations, and open triangles are capillary dried blood spot concentrations. Solid lines represent locally weighted least-squares regressions, based on both capillary and venous data.

FIG 2

Visual predictive plots of piperaquine in pregnant women in Kenya (A) and Indonesia (B). Open markers represent observed concentrations. Solid and dashed lines represent the median and the 5th and 95th percentiles of the observations. Shaded areas represent the predicted 95% confidence intervals of each percentile.

FIG 3

Observed piperaquine trough concentrations (C_min) and predicted piperaquine maximum concentrations (C_max). (A) Plasma trough concentrations in Kenyan pregnant women; (B) capillary DBS trough concentrations in Indonesian pregnant women; (C) plasma piperaquine maximum concentrations in Kenyan pregnant women; (D) capillary DBS piperaquine maximum concentrations in Indonesian women. The box-and-whisker plots represent the medians with interquartile ranges and the 95% prediction intervals. The horizontal red lines represent a target piperaquine plasma concentration in pregnant women of 10.3 ng/ml (equivalent to 26.9 mg/ml capillary DBS concentrations) (24).

FIG 4

Simulation of monthly piperaquine dosing in pregnant women receiving IPTp. (A) Venous piperaquine plasma concentrations versus time (n = 1,000). The blue solid line represents the predicted median piperaquine concentration-time profile, and the shaded area represents the 95% prediction interval. The horizontal dashed black line represents the proposed target plasma concentration of 10.3 ng/ml (24). (B) Proportion of patients with piperaquine trough concentrations below the target concentration (n = 1,000 individuals; 1,000 replicates). The box-and-whisker plots represent the medians with interquartile ranges and the 95% prediction intervals of the simulated concentrations. (C) Cumulative proportion of patients with plasma concentrations below the target concentrations (10.3 ng/ml) (blue solid lines) and 95% prediction intervals (blue shaded areas). The triple vertical lines represent monthly dosing. The gray-shaded areas represent a 1-week time interval, preceding a dose in which submicroscopic infection can be eliminated by the next IPTp treatment round.