This study reports on SP pharmacokinetic parameters in young African children with uncomplicated P. falciparum malaria in the context of combination therapies, and confirmed the lower SP concentrations previously reported for this age group when compared with adult malaria patients . There was no statistically significant difference between sulphadoxine and pyrimethamine concentrations (at day 1, day 3 and day 7), AUC and elimination half-life between the SP monotherapy and SP+AS arms. AS having no impact on these SP pharmacokinetic parameters is consistent with a study previously reported in healthy adults when AS was administered concomitantly with SP  and is reassuring, supporting the use of AS in combination with SP. However, a higher volume of distribution of pyrimethamine in the SP + AS arm when compared to SP monotherapy arm was observed in this study [median 5.60 vs. 4.65 L/kg; p = 0.030 (Table 3)].
Although adding amodiaquine to SP had no effect on sulphadoxine pharmacokinetic parameters, a significant decrease in the apparent volume of distribution and elimination half-life of pyrimethamine in the SP+AQ arm was observed. However, this did not result in a significant change in pyrimethamine concentrations in the blood in SP+AQ arm over the critical initial seven days of treatment nor the AUC. The absence of a substantial PK interaction in our study population supports the effectiveness of SP+AQ in IPTc [7, 10] and in uncomplicated falciparum malaria treatment in children under five . The effect of the shorter pyrimethamine elimination half-life could possibly reduce the post-treatment prophylactic effect of sulphadoxine-pyrimethamine plus amodiaquine as resistance to these partner drugs increases.
Day-7 concentrations of sulphadoxine and pyrimethamine are a good surrogate measure of their respective total whole blood AUCs  and Day 7 concentration is a predictor of treatment outcome . Day7 pyrimethamine concentration observed in this study was slightly higher in SP+AQ arm, but this difference was not statistically significant (Figure 3). When compared with SP Day-7 capillary blood concentrations previously published for children aged 2-5 years in southern Africa [sulphadoxine median 31.3 (IQR 19.7-52.0); pyrimethamine median 70.3 (IQR 39.0-101.9)], day-7 concentrations in young Malian children were similar for sulphadoxine, but appeared lower for pyrimethamine.
The vast majority of our patients achieved maximum concentrations of both sulphadoxine and pyrimethamine on day 1. However, the exact Cmax and Tmax could not be determined precisely because of limited sampling frequency. The concentration of artesunate could not be quantified because of the sampling methodology used, and the concentrations and pharmacokinetic parameters of amodiaquine (when administered with SP) will be reported separately.
The two children who were retreated with the full dose after vomiting within 30 minutes of SP administration had approximately double the median SP concentrations on day 1, suggesting that further data is needed to inform optimal dosing in patients with early vomiting.
In this study conducted in Mali in 2004-2006, SP or its combination with AS or AQ remained highly effective with more than a 95% adequate clinical and parasitological response rate. Although this level of efficacy of SP when administered alone or in combination with either AS or AQ is quite high in comparison with data from Eastern or Southern Africa [20, 21], these rates are common in West Africa [22–24] and may reflect the lower frequency of dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) mutations associated with SP resistance [25, 26]. Probably because of their strong synergy, the minimum effective concentrations (MEC) of sulphadoxine and/or pyrimethamine have not been clearly defined. In Gabon, where the prevalence of DHFR triple mutation was ~70%, day 3 concentrations associated with treatment success were 100 μg/mL for sulphadoxine and 175 ng/mL pyrimethamine . Of the 109 children in this study, only 4 (3.7%) and 40 (36.7%) achieved these 'therapeutic' day-three concentrations of sulphadoxine and pyrimethamine, respectively. This might suggest that as dhfr/dhps mutations accumulate the SP concentrations achieved may be insufficient to ensure an adequate clinical and parasitological response rate as recently described in Malawi .