Amodiaquine Dosage and Tolerability for Intermittent Preventive Treatment To Prevent Malaria in Children

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.Relatively minor adverse reactions to antimalarials that may be acceptable when malaria illness is being treated may not be acceptable when drugs are used on a large scale for intermittent preventive treatment in children (IPTc), when the majority of recipients will be healthy. The response of children and their parents to adverse reactions, even those relatively minor in nature, could limit the uptake of IPTc as a strategy. It is, therefore, important to minimize the side effects associated with this intervention.Sulfadoxine-pyrimethamine combined with amodiaquine (SP-AQ) has been identified as a highly efficacious regimen for treatment of malaria (4, 8, 11, 23-26) and for IPT (5, 14). However, when used for IPT in children, SP-AQ has been associated with an increased incidence of mild adverse events, particularly vomiting and fever, in the days following the IPT course (5, 14). One answer to this problem would be to use other antimalarials as the partner drug to SP, which has been shown extensively to be safe and well tolerated when used for intermittent preventive treatment (1, 6). Long-acting antimalarials are preferable to artemisinins for IPT because they provide a longer period of posttreatment prophylaxis, which is central to the protection given by IPT (4a, 19). Piperaquine has been identified as a promising partner drug (5) (K. Bojang et al., unpublished data). However, SP-piperaquine is currently not licensed as a combination for use in IPT and there may be some delay in obtaining sufficient safety and pharmacokinetic data to allow deployment of this combination. Any measures that can improve the tolerability of SP-AQ for use in the meantime could therefore be beneficial.One way in which the tolerability of SP-AQ might be improved is by ensuring that children receive as accurate a dose as possible. The recommended dose for a course of amodiaquine is 30 mg amodiaquine base/kg body weight over 3 days, i.e., 10 mg/kg/day (22). Dosing by weight is therefore the ideal approach, but limitations in resources and training may make this impractical in resource-poor areas (2, 9). Weighing children may be particularly problematic with a large-scale preventive intervention such as IPTc, in which many children will be treated in a short space of time and mobility of health workers may be important for successful delivery (Bojang et al., unpublished data). Development of an accurate dose-for-age schedule would thus be advantageous. Dose-for-age has already been developed for amodiaquine as part of a fixed dose combination with artesunate used for treatment of malaria cases (13, 16), but the priorities may be different for IPT because most children will not be unwell when they are treated. Regimens could be developed specifically for use in IPT.The regimen used in previous and ongoing trials of IPTc in Senegal consists of one 200-mg AQ tablet for children aged 2 years or over and half a 200-mg tablet for younger children (5; www.clinicaltrials.gov, identifier {"type":"clinical-trial","attrs":{"text":"NCT00712374","term_id":"NCT00712374"}}NCT00712374). Since health workers are used to dichotomizing the dose given to children at 2 years of age, replacing the 200-mg tablet with one with lower AQ content might be a simple way to improve dosing accuracy. One option would be to use a 153-mg AQ tablet that is currently available for treatment. An alternative age-based regimen for amodiaquine was developed using a large anthropometric data set by Taylor et al. (16) and was recently shown to be well tolerated (13). The AQ doses for this regimen are 67.5 mg for infants as a single tablet and 135 mg for children over 12 months (as two 67.5-mg tablets). The chief problem with this regimen is that children aged between 12 and 23 months are more likely to be overdosed (16). Amending this AQ regimen to include a separate dose for 12- to 23-month-old children might be feasible within an IPT program. Because SP and AQ can both be manufactured to contain any specified amount of the active component, a more flexible option would be to manufacture tablets specifically for seasonal IPT with the optimal concentration of AQ for dosing by age.This study investigated the accuracy of the amodiaquine dosing strategy used in two recent trials of IPTc using SP-AQ, the relationship between dosage and adverse events, and the potential for alternative amodiaquine regimens to reduce overdosing and adverse events.