Pharmacometric and Electrocardiographic Evaluation of Chloroquine and Azithromycin in Healthy Volunteers

Figures

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  Figure 1. Visual predictive plots of the final pharmacokinetic model of plasma chloroquine concentrations. Solid and dashed lines represent the median, 5th, and 95th percentiles of the observations. Shaded areas represent the predictive 95% confidence intervals of each percentile.

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  Figure 2. Visual predictive plots of the final pharmacokinetic model of plasma azithromycin concentrations, stratified by treatment arm. Solid and dashed lines represent the median, 5th, and 95th percentiles of the observations. Shaded areas represent the predictive 95% confidence intervals of each percentile.

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  Figure 3. Electrocardiographic changes after the last day of drug administration, stratified by treatment arm. (a) ΔRR intervals, (b) ΔPR intervals, (c) ΔQRS intervals, (d) ΔJTc intervals, and (e) ΔQTc intervals vs. time after dose (c refers to subject‐specific individual heart rate‐correction).

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  Figure 4. Visual predictive plot of the relationship between the prolongation of electrocardiographic intervals and the corresponding plasma chloroquine concentrations (a–d) and placebo‐adjusted electrocardiographic intervals for the corresponding plasma chloroquine concentrations (e–h): ΔPR (a), ΔQRS (b), ΔJTc (c), ΔQTc (d) ΔΔPR (e), ΔΔQRS (f), ΔΔJTc (g), and ΔΔQTc (h). Solid and dashed red lines represent the median, 5th, and 95th percentiles of the observations. Solid blue lines and equations show the simple linear regression model fit. Shaded areas in panel a–d represent the 95% confidence intervals (CIs) of predictions at each percentile, based on the final population pharmacodynamic model. Solid lines and shaded areas in panel e–h represent the median placebo‐adjusted electrocardiographic intervals and 90% CIs.

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  Figure 5. Boxplot of the maximum electrocardiographic intervals (a) and the maximum electrocardiographic prolongations (b) between each treatment arm. The JT, and QT intervals have been individually heart‐rate corrected. The mean (SD; range) of the maximum changes on PR, QRS, JTc, and QTc intervals in all chloroquine administration arms are 18.4 (8.80; −1.33 to 39.33) ms, 12.1 (3.55; 3.66 to 21.3) ms, 30.9 (10.8; −2.02 to 61.8) ms, and 38.8 (11.4; 6.66 to 69.11) ms, respectively.