Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia

Abstract

Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.).

Keywords: POPPK; QT prolongation; antimalarial agents; cardiac safety; piperaquine.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Plots of observed maximum concentrations of piperaquine from three clinical studies evaluating DP (2010 to 2013). Blue, red, and green symbols, data from the 2010, 2012, and 2013 studies, respectively; circles, 2DP regimen; diamonds, 3DP regimen; horizontal bars, median and interquartile ranges; value above each column, the median piperaquine concentration; red bars above the columns, individual comparisons of statistical significance (**, significant differences [P < 0.01]; ****, very highly significant differences [P < 0.0001]).

FIG 2

Plots of the medians and interquartile ranges of the observed QTcFm at 0, 24, 48, and 52 h after the first dose of DP or placebo (A) and the change in QTcFm over the baseline at 4, 24, 28, 48, and 52 h after the first dose (B) from the three clinical trials conducted between 2010 and 2013 in northern Cambodia. Light blue, orange, green, pink, dark blue, and red, data for times of 0, 4, 24, 28, 48, and 52 h after the first dose, respectively; horizontal bars, median and interquartile ranges; value above each column, median; red bars above the columns, individual comparisons of statistical significance (**, significant differences [P < 0.01]; ****, very highly significant differences [P < 0.0001]). Note that the volunteers in the 2010 and 2013 studies were treated for uncomplicated malaria, while those in the 2012 study were healthy volunteers administered DP as prophylaxis. The 2010 study collected trough drug levels and EKG results only at 24 and 48 h postdosing.

FIG 3

Basic goodness-of-fit plots for the final piperaquine population model. (A, B) Observed concentrations were plotted against population predicted natural logarithm-transformed concentrations (A) and against individual predicted concentrations (B) and compared to the line of identity (solid line). (C, D) Conditional weighted residuals were plotted against population predicted concentrations (C) and the time after dose administration (D).

FIG 4

Visual predictive check of the final piperaquine model. Circles, observed data; red and black lines, 5th, 50th, and 95th percentiles of the observed and predicted data, respectively. The concentrations were transformed into their natural logarithms. The second peak at about 720 h (30 days) represents the second month of dosing from the DP prophylaxis study in 2012 in a small subset of subjects.

FIG 5

(A to C) Plots of the plasma piperaquine concentration versus ΔQTcFm over the QTcFm at the baseline. Pink, green, and yellow circles, results for volunteers receiving the normal 2DP regimen, volunteers receiving the normal 3DP regimen, and volunteers who were stopped from participating in the study, respectively. (D) Plot of the overall observed change in QTcFm over that at the baseline versus the plasma piperaquine concentration from linear slope-intercept modeling. Red circles, observed data; blue line, predicted values. The slope estimate was 0.05 ms per ng/ml of piperaquine (RSE = 5.26%) with a baseline intercept of 6.55 ms (RSE = 10.1%) and a standard deviation for the additive residual error of 22.4.

FIG 6

Effects of baseline serum potassium concentration (A), baseline serum magnesium concentration (B), time since the previous meal (C), and baseline QTcFm on the maximum change in the manually read QTcF (max ΔQTcFm) (D) for volunteers receiving dihydroartemisinin-piperaquine in northern Cambodia. ns, no significant difference.