Sulfadoxine-pyrimethamine (SP) has been widely used in recent years to treat acute uncomplicated
Plasmodium falciparum malaria. Risk factors for SP therapeutic failure include young age, subtherapeutic SP concentrations, and resistance-conferring genetic mutations in parasite target
enzymes. A substantial proportion of patients are able to clear genetically highly resistant P. falciparum genotypes. To determine whether blood SP concentrations independently affect the patient's ability to clear resistant genotypes, we compared SP pharmacokinetics of cases of adequate clinical and parasitological response (ACPR) with cases of treatment failure (TF). When patients with ACPR and TF were compared, mean values were similar for the day 3 blood
pyrimethamine (205 ng/ml versus 172 ng/ml; P = 0.25) and estimated maximum
sulfadoxine (79 +/- 6.52 versus 69 +/- 6.27 mug/ml; P = 0.60) concentrations, for
sulfadoxine terminal-phase elimination half-lives (7.15 versus 6.41 days; P = 0.42), and for the extents of
sulfadoxine absorption (areas under the concentration-time curve of 932 +/- 100 versus 888 +/- 78.9 mug day ml(-1); P = 0.72). Among patients infected with the quintuple resistant parasites, day 3 blood
pyrimethamine concentrations were higher in those who cleared the
infection than in those who did not (305 +/- 35.4 versus 228 +/- 21.7 ng/ml; P = 0.037). Within this subgroup, this finding remained significant after adjusting for endogenous
folate levels, age, site, and resistance-conferring mutations (odds ratio: 1.011 [1.003 to 1.024]; P = 0.018). However, as a subgroup analysis, our biologically plausible observation that higher blood
pyrimethamine concentrations enhance the ability of patients to clear resistant P. falciparum should be interpreted with caution and needs further validation.