Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis

Abstract

AimsTo develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis. MethodsChildren were treated with PYR (1.25 mg kg -1 ) and SDX (25 mg kg -1 ) (Fansidar ® ) plus folinic acid (Lederfoline ® 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-per formance liquid chromatogrphy. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. ResultsEighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution ( V ) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day -1 and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day -1 and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX. ConclusionThis study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.

Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women

“…In particular, the median t 1/2␤ s of 18.8 and 9.9 days for pregnant and nonpregnant women, respectively, are higher than previously reported values, which have ranged from 2.9 to 5.1 days in adults (3,5,12,14,19,25,32,34,35) and from 2.8 to 4.5 days in children (3,9,30,38). Most other studies have utilized a single-compartment model (3,9,14,30,32) and/or sampling durations of Յ14 days (12,14,32,38). In one study that attempted to measure PYR concentrations to 42 days, 38% of plasma concentration data was excluded from analysis because levels were either undetectable or below the 10-g/liter LOQ of the LCMS assay (3).…”

“…In contrast to SDOX, the PK parameters for PYR in both our patient groups differed markedly from those found in a wide variety of clinical and ethnogeographic settings (3,5,9,11,12,14,19,21,25,30,32,34,35,38). In particular, the median t 1/2␤ s of 18.8 and 9.9 days for pregnant and nonpregnant women, respectively, are higher than previously reported values, which have ranged from 2.9 to 5.1 days in adults (3,5,12,14,19,25,32,34,35) and from 2.8 to 4.5 days in children (3,9,30,38). Most other studies have utilized a single-compartment model (3,9,14,30,32) and/or sampling durations of Յ14 days (12,14,32,38).…”

“…All other chemicals were of analytical or high-pressure liquid chromatography grade. Extraction of SDOX and NASDOX from 50 l of plasma and PYR from 500 l of plasma was by previously published methods (10,30). Separations were performed on a 5-m, 250-mm-by-4-mm (internal diameter) Lichrospher RP Select B column (Merck) at 30°C.…”

“…The treatment with the best evidence for use as IPTp is sulfadoxine (SDOX) plus pyrimethamine (PYR) (SP) (22,26,31), but its effectiveness appears paradoxical given the component drugs have a relatively short elimination half-life (t 1/2␤ ), specifically 6 to 11 days for SDOX (12,19,21,24,25,32,34,35) and 3 to 5 days for PYR (3,5,9,11,12,14,19,21,25,30,32,34,35,38). SDOX is acetylated by the enzyme N-acetyltransferase 2.…”

In Vitro Susceptibility of Various Genotypic Strains of Toxoplasma gondii to Pyrimethamine, Sulfadiazine, and Atovaquone

“…In addition, the relationship between in vitro susceptibility and clinical resistance remains to be examined. Pharmacokinetic studies have revealed marked individual variations in pyrimethamine concentrations in human immunodeficiency virus (HIV)-infected patients (20,49) and in children treated for congenital toxoplasmosis (11,33,44,47). In HIV-infected patients with toxoplasmic encephalitis, a positive relationship between clinical and radiological responses and median atovaquone plasma concentrations has been shown (46).…”