Amodiaquine dosage and tolerability for intermittent preventive treatment to prevent malaria in children

Abstract

Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the amodiaquine component is not always well tolerated. We determined the association between amodiaquine dosage by body weight and mild adverse events (AEs) and investigated whether alternative age-based regimens could improve dosing accuracy and tolerability, using data from two trials of IPTc in Senegal, one in which AQ dose was determined by age and the other in which it was determined by weight category. Both dosage strategies resulted in some children receiving AQ doses above the recommended therapeutic range. The odds of vomiting increased with increasing amodiaquine dosage. In one study, incidence of fever also increased with increasing dosage. Anthropometric data from 1,956 children were used to predict the dosing accuracy of existing and optimal alternative regimens. Logistic regression models describing the probability of AEs by dosage were used to predict the potential reductions in mild AEs for each regimen. Simple amendments to current AQ dosing schedules based on the child's age could substantially increase dosing accuracy and thus improve the tolerability of IPTc using SP-amodiaquine in situations where weighing the child is impractical.

FIG. 1.

Amodiaquine dosage in Keur Soce by age group. Dose is shown in mg/kg/day. Solid lines indicate the target dosing range for AQ (7.5 to 15 mg/kg/day for 3 days). The dashed line indicates the median daily dose.

FIG. 2.

Amodiaquine and sulfadoxine dosage in the SP-AQ group in Niakhar. Dose is shown in mg/kg/day. Solid lines indicate the recommended dosing range (7.5 to 15 mg/kg/day AQ and 25 to 70 mg/kg SP). The dashed line indicates the median dose.

FIG. 3.

Predicted probability of vomiting or fever by AQ dose. The predicted probability (plus 95% CI) is shown for vomiting (ever vomited) or having fever (ever fever) at any of the three IPT doses according to the AQ dose received. For clarity, the predicted line for the effect of dose unadjusted for age is shown.

FIG. 4.

Dosing accuracy with existing and optimal alternative regimens. Histograms of the predicted dosing accuracy with regimens used in the two IPTc trials, existing alternative regimens, and optimum regimens are shown. Tablet strengths and age cutoffs for the regimens are given in the text. Dose is shown in mg/kg/day. Solid lines indicate the target dosing range for AQ. The dashed lines indicate the median daily dose.