Cardiovascular concentration-effect relationships of amodiaquine and its metabolite desethylamodiaquine: Clinical and preclinical studies.
Br J Clin Pharmacol
; 89(3): 1176-1186, 2023 03.
Article
en En
| MEDLINE
| ID: mdl-36256474
ABSTRACT
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Malaria
/
Antimaláricos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
País/Región como asunto:
Africa
Idioma:
En
Revista:
Br J Clin Pharmacol
Año:
2023
Tipo del documento:
Article
País de afiliación:
Tailandia