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

BACKGROUND: Amodiaquine is a 4-aminoquinoline antimalarial used extensively for the treatment and prevention of malaria. Orally administered amodiaquine is largely converted to the active metabolite desethylamodiaquine. Oral amodiaquine can cause bradycardia, hypotension, and electrocardiograph (ECG) QT interval prolongation in animals and humans but the relationship of these changes to drug concentrations is not well characterised. METHODS: We conducted a secondary analysis of data from a pharmacokinetic study of the cardiac safety of amodiaquine (10mg/kg/day over 3 days) in 54 Kenyan adults (≥18 years) with uncomplicated malaria. Non-linear mixed effects modelling was used to assess amodiaquine and desethylamodiaquine concentration-effect relationships for vital sign (pulse rate, blood pressure) and ECG 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. FINDINGS: Amodiaquine and desethylamodiaquine caused concentration-dependent mean decreases in pulse rate (1.9beats/minute per 100nmol/L), supine systolic blood pressure (1.7mmHg per 100nmol/L), erect systolic blood pressure (1.5mmHg per 100nmol/L), and erect diastolic blood pressure (1.4mmHg per 100nmol/L). The mean QT interval prolongation was 1.4milliseconds per 100nmol/L irrespective of correction factor used after adjustment for residual heart rate dependency. There was no significant independent 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=7) and desethylamodiaquine (n=8) at 3μmol/litre (amodiaquine: 10% ± 2%; desethylamodiaquine: 12% ± 3%) and 10μmol/litre (amodiaquine: 50% ± 7%; desethylamodiaquine: 46% ± 6%) concentrations with no significant difference in potency between the two compounds. INTERPRETATION: Amodiaquine and desethylamodiaquine have concentration-dependent effects on heart rate, blood pressure, and ventricular repolarisation.