Pooled Multicenter Analysis of Cardiovascular Safety and Population Pharmacokinetic Properties of Piperaquine in African Patients with Uncomplicated Falciparum Malaria

Abstract

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicenter trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90-ms mean QTc prolongation per 100-ng/ml increase in piperaquine concentration. The effect of piperaquine on absolute QTc interval estimated a mean maximum QTc interval of 456 ms (50% effective concentration of 209 ng/ml). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98 to 2.46% risk of having QTc prolongation of >60 ms in all treatment settings. Although piperaquine administration resulted in QTc prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern. (This study has been registered at ClinicalTrials.gov under identifier NCT02199951.).

Keywords: QT prolongation; antimalarial agents; cardiovascular safety; malaria; piperaquine; population pharmacokinetic-pharmacodynamic model; population pharmacokinetics.

Copyright © 2020 Wattanakul et al.

Figures

FIG 1

Visual predictive check of the final piperaquine pharmacokinetic model. The open circles represent the observed piperaquine concentrations. Solid red lines represent the 50th percentiles of the observations, and dashed red lines represent the 5th and 95th percentiles of the observations. The shaded areas represent the 95% confidence intervals of each simulated percentile (n = 2,000).

FIG 2

Observed QTcSSB intervals, stratified by ECG measurement schedule. The solid lines and error bars represent the medians and interquartile ranges of QTcSSB intervals recorded at each ECG measurement occasion, stratified by QTc interval threshold categories.

FIG 3

Diagnostics of the final pharmacokinetic-pharmacodynamic model. (A and B) Goodness-of-fit plots showing observed QTcSSB interval versus individually predicted QTcSSB interval (A) and conditionally weighted residual versus time after dose (B). The solid black lines represent the line of identity, and the dashed red lines represent a local polynomial regression fitting of all observations (i.e., trend line). (C) Visual predictive check of the model describing the relationship between piperaquine concentrations and absolute QTcSSB intervals using an Emax function (n = 2,000). The open circles represent the observations. The solid red line represents the 50th percentile of the observations, and dashed red lines represent the 5th and 95th percentiles of the observations. The shaded areas represent the 95% confidence intervals of each simulated percentile.

FIG 4

Predicted maximum QTcSSB intervals after different dosing regimens, simulated from the final pharmacokinetic-pharmacodynamic model. The box plots represent the simulated maximum QTcSSB interval, stratified by body weight, in children weighing 5 to 25 kg (data on adults are presented in Fig. S5 in the supplemental material) after receiving the old and new dosing regimen for acute malaria treatment (3-day regimen) (A) and mass drug administration (monthly 3-day regimen) (B). The dashed red lines represent an absolute QTc interval regulatory safety cutoff of 500 ms.

FIG 5

Probability density of maximum QTcSSB intervals and ΔQTcSSB intervals after different dosing regimens, simulated from the final pharmacokinetic-pharmacodynamic model. The graphs shows the probability density distribution of maximum QTcSSB intervals and maximum ΔQTcSSB intervals based on a total of 480,000 simulated patients after receiving the old (gray solid lines) and new (red solid lines) dosing regimens for acute malaria treatment (3-day regimen) (A and B) and for mass drug administration (monthly 3-day regimen) (C and D).