Safety, Pharmacokinetics, and Mosquito-Lethal Effects of Ivermectin in Combination With Dihydroartemisinin-Piperaquine and Primaquine in Healthy Adult Thai Subjects

Abstract

Mass administration of antimalarial drugs and ivermectin are being considered as potential accelerators of malaria elimination. The safety, tolerability, pharmacokinetics, and mosquito-lethal effects of combinations of ivermectin, dihydroartemisinin-piperaquine, and primaquine were evaluated. Coadministration of ivermectin and dihydroartemisinin-piperaquine resulted in increased ivermectin concentrations with corresponding increases in mosquito-lethal effect across all subjects. Exposure to piperaquine was also increased when coadministered with ivermectin, but electrocardiograph QT-interval prolongation was not increased. One subject had transiently impaired liver function. Ivermectin mosquito-lethal effect was greater than predicted previously against the major Southeast Asian malaria vectors. Both Anopheles dirus and Anopheles minimus mosquito mortality was increased substantially (20-fold and 35-fold increase, respectively) when feeding on volunteer blood after ivermectin administration compared with in vitro ivermectin-spiked blood. This suggests the presence of ivermectin metabolites that impart mosquito-lethal effects. Further studies of this combined approach to accelerate malaria elimination are warranted.

Figure 1

Liver enzymes associated with drug administration of ivermectin, dihydroartemisinin‐piperaquine, and primaquine in one subject. Aspartate transaminase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) values in one female volunteer following administration of (a) ivermectin plus dihydroartemisinin‐piperaquine (DHA‐PQP) and (b) ivermectin plus DHA‐PQP plus primaquine. Dashed lines demarcate adverse events grading scale for female subjects at Mahidol Hospital for Tropical Diseases.

Figure 2

Electrocardiographic effects, stratified by treatment regimen. Open circles represent observed study‐corrected QT‐interval prolongations (ΔQTcS) and associated measured drug concentrations at those particular time points. Solid red lines represent the mean regression line and the shaded areas represent the 95% confidence interval of the mean slope. Dashed black lines represent zero ΔQTcS effect. DHA‐PQP, dihydroartemisinin‐piperaquine.

Figure 3

Drug–drug interaction effects, stratified by drug and treatment regimen. Graphs represent Forest plots of geometric mean ratios of pharmacokinetic parameters (circles) and associated 90% confidence intervals around these ratios (bars). The solid vertical lines represent no interaction, whereas vertical dashed lines represent an effect of ± 25% relative difference, deemed to represent a clinical relevant effect. AUC_T, area under the concentration‐time curve from time zero to the last measured concentration; C_max, peak plasma concentration; DHA‐PQP, dihydroartemisinin‐piperaquine; T_max, time to reach maximum concentration.

Figure 4

Mosquito lethal effects of ivermectin, across all drug regimens, stratified by Anopheles dirus (a) and Anopheles minimus (b). Filled symbols represent the cumulative mean mosquito mortality at 10 days post‐blood meal, across the different ivermectin‐containing drug regimens, at each blood collection time point. Bars represent the 95% confidence intervals around these means. DHA‐PQP, dihydroartemisinin‐piperaquine.

Figure 5

Mosquito lethal effects of ivermectin, after membrane feeding to Anopheles dirus (a, b) and Anopheles minimus (c, d), using ivermectin‐spiked blood a, c and human volunteer blood after ivermectin administration b, d. In vitro spiked blood a, c represents healthy human blood spiked with known concentrations of ivermectin reference standard. In vivo volunteer blood b, d represents human volunteer blood collected in healthy volunteers at various time points after oral administration of ivermectin (400 μg/kg), and drug concentrations measured using liquid chromatography mass spectrometry. Open circles represent cumulative mosquito mortality 7 days after blood meal ingestion. Solid red lines represent the mean concentration‐response relationship and the dashed red lines represent the 95% confidence interval associated with the nonlinear fit. Dashed black lines represent the estimated minimum effects based on control mosquito mortality, and fixed maximum effects of 100% mortality.

Figure 6

Pharmacokinetic and pharmacodynamic effects of ivermectin. Observed ivermectin concentration (black, left y‐axis) and Anopheles dirus mosquito mortality (red; right y‐axis) plotted vs. time. Solid lines represent median values and shaded areas represent the interquartile range (25–75th percentile). The dashed black line represents the An. dirus in vitro 7‐day‐lethal concentration 50%‐value (57.65 ng/mL).