Cardiovascular Concentration‐Effect Relationships of Amodiaquine and its Metabolite Desethylamodiaquine: Clinical and Pre‐clinical Studies

Aims Amodiaquine is a 4‐aminoquinoline used extensively for the treatment and prevention of malaria. Orally administered amodiaquine is largely converted to the active metabolite desethylamodiaquine. Amodiaquine can cause bradycardia, hypotension, and electrocardiograph QT interval prolongation, but the relationship of these changes to drug concentrations is not well characterized. Methods We conducted a secondary analysis of a pharmacokinetic study of the cardiac safety of amodiaquine (10 mg base/kg/day over 3 days) in 54 Kenyan adults (≥18 years) with uncomplicated malaria. Nonlinear mixed effects modelling was used to assess amodiaquine and desethylamodiaquine concentration–effect relationships for vital sign (pulse rate, blood pressure) and electrocardiograph interval (QT, QRS, PR) outcomes. We also measured the spontaneous beating heart rate after cumulative dosing of amodiaquine and desethylamodiaquine in isolated mouse atrial preparations. Results Amodiaquine and desethylamodiaquine caused concentration‐dependent mean decreases in pulse rate (1.9 beats/min per 100 nmol/L; 95% confidence interval: 1.5–2.4), supine systolic blood pressure (1.7 mmHg per 100 nmol/L; 1.2–2.1), erect systolic blood pressure (1.5 mmHg per 100 nmol/L; 1.0–2.0) and erect diastolic blood pressure (1.4 mmHg per 100 nmol/L; 1.0–1.7). The mean QT interval prolongation was 1.4 ms per 100 nmol/L irrespective of correction factor after adjustment for residual heart rate dependency. There was no significant effect of drug concentration on postural change in blood pressure or PR and QRS intervals. In mouse atria, the spontaneous beating rate was significantly reduced by amodiaquine ( n = 6) and desethylamodiaquine ( n = 8) at 3 μmol/L (amodiaquine: 10 ± 2%; desethylamodiaquine: 12 ± 3%) and 10 μmol/L (amodiaquine: 50 ± 7%; desethylamodiaquine: 46 ± 6%) concentrations with no significant difference in potency between the 2 compounds. Conclusion Amodiaquine and desethylamodiaquine have concentration‐dependent effects on heart rate, blood pressure, and ventricular repolarization.