Association between the pharmacokinetics and in vivo therapeutic efficacy of sulfadoxine-pyrimethamine in Malawian children.
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.
Dzinjalamala
Fraction K
FK
University of Cape Town, Division of Clinical Pharmacology, K50 Old Main Building, Groote Schuur Hospital, Cape Town 7925, South Africa.
Macheso
Allan
A
Kublin
James G
JG
Taylor
Terrie E
TE
Barnes
Karen I
KI
Molyneux
Malcolm E
ME
Plowe
Christopher V
CV
Smith
Peter J
PJ
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008295:Malawi; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D011739:Pyrimethamine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013413:Sulfadoxine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017211:Treatment Failure; D016896:Treatment Outcome
D000962:Antimalarials; D004338:Drug Combinations; D013413:Sulfadoxine; D011739:Pyrimethamine