Population pharmacokinetics of pyrimethamine and sulfadoxine in children treated for congenital toxoplasmosis.
The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis. A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling. PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months. Drug concentrations were measured by high-performance liquid chromatography. A total of 101 measurements in serum were available for both drugs. Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h(-1), 4.379 liters/kg, 0.00839 h(-1), and 5.5 days for PYR and 1.659 h(-1), 0.392 liters/kg, 0.00526 h(-1), and 6.6 days for SDX, respectively. Wide interindividual variability was observed. The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively. Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children. Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight. The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established. A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children.
Corvaisier
Stéphane
S
Department of Pharmacy, Croix-Rousse Hospital, 103 Grande Rue de la Croix-Rousse, 69317 Lyon Cedex 04, France.
Charpiat
Bruno
B
Mounier
Cyril
C
Wallon
Martine
M
Leboucher
Gilles
G
Al Kurdi
Mounzer
M
Chaulet
Jean-François
JF
Peyron
François
F
D000981:Antiprotozoal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001499:Bayes Theorem; D001835:Body Weight / Q000502:physiology; D002648:Child; D002851:Chromatography, High Pressure Liquid; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008954:Models, Biological; D011153:Population; D011739:Pyrimethamine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013413:Sulfadoxine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014123:Toxoplasmosis / Q000188:drug therapy / Q000378:metabolism*
D000981:Antiprotozoal Agents; D013413:Sulfadoxine; D011739:Pyrimethamine