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.

Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial

“…Vomiting was the most common side effect of SMC. The age pattern of vomiting in children who received SMC is consistent with a dose-related risk of vomiting, as has been reported in other studies of SMC in African children [ 17 ]. The overall rate of outpatient attendance with SMC-related vomiting was low.…”

Evaluating artesunate-amodiaquine deployment, efficacy and safety: an in silico pharmacological model

“…Patients overdosed with AQ are more prone to vomiting than those receiving the appropriate dose (76), a side effect that can make patients and caregivers reluctant to administer treatment (61). When treating children with AS-AQ, overdosing of the AQ component is a particular concern regardless of whether children are dosed according to their age or weight.…”

The Pharmacogenetics of the Antimalarial Amodiaquine

“…The few data available suggest that the AQ adverse events are drug dose dependent (Hatton et al, 1986) (Cairns et a., 2010). Although drug associated severe and lethal reactions have not been generally observed in AQ regimens for the treatment of uncomplicated malaria (Olliaro et al, 1996) (Olliaro and Mussano, 2003), mild events are relatively frequent, being a threat for full regimen compliance (e.g.…”

“…more optimized) AQ dosing, with values below the conventional 10 mg/Kg, or through a different regimen schedule. As the incidence of side effects is dose dependent (Cairns et al, 2010), individualized treatment would be expected to reduce those events. The success of such strategies could boost the patient's (and specially their guardians) trust on the treatment, leading to increased compliance to the full dosing regimen.…”

“…Mild events include mainly gastro-intestinal effects, particularly vomiting (Brasseur et al, 1999) (Adjuik et al, 2002) (Cairns et al, 2010) (Nankabirwa et al, 2010) and self-reported abdominal pain (Parikh et al, 2007) (Bojang et al, 2010), both frequently observed in amodiaquine efficacy clinical trials. Most importantly, several studies have noted situations of (clinically asymptomatic) neutropenia upon AQ therapies in subsets of the treated population (Staedke et al, 2001) (Adjuik et al, 2002).…”