title: Population pharmacokinetics of sulfadoxine and pyrimethamine in Malawian children with malaria.
abstract: In addition to parasite resistance, inadequate levels of exposure to antimalarial drugs may contribute to treatment failure. We developed population pharmacokinetic (PK) models to describe the distribution of sulfadoxine (SDX) and pyrimethamine (PYM) in children with uncomplicated malaria in Malawi. The concentration levels of antimalarial drugs in whole blood were determined using high-performance liquid chromatography. We found no evidence of underdosing in children as compared with adults; the children had drug exposure levels similar to those described in adults. Treatment failure was more likely in children with lower PYM concentrations on day 14 (P = 0.024), and there was a trend for lower SDX concentrations on day 14 (P = 0.061). SDX and PYM concentrations at levels predictive of treatment failure have been identified at day 14. Less than one-third of the children displayed drug concentration levels above these thresholds after receiving the recommended SDX-pyrimethamine (SP) dose. Our findings suggest that PK factors contributed to the observed high rate of treatment failure, and we therefore recommend a higher SP dose for children under the age of 5 years.
authors.affiliation: Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Bell
authors.forename: S K
authors.initials: SK
authors.lastname: Nyirongo
authors.forename: M
authors.initials: M
authors.lastname: Mukaka
authors.forename: M E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: P A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: S A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D000367:Age Factors; D000962:Antimalarials / Q000493:pharmacokinetics*; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy; D008297:Male; D008954:Models, Biological; D011739:Pyrimethamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013413:Sulfadoxine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine