Population Pharmacokinetics of Pyrimethamine and Sulfadoxine in Children Treated for Congenital Toxoplasmosis

Abstract

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.Toxoplasma gondii is a ubiquitous intracellular protozoan parasite. Infection during pregnancy can result in fetal infection, leading to severe congenital defects such as hydrocephalus, mental retardation, and retinochoroiditis that may be present at birth or may develop later in life (36). Although no well-controlled clinical trials have been carried out to assess its efficacy and safety in children, early treatment is believed to prevent late-onset sequelae. A bibliographical analysis revealed up to 20 different therapeutic antiparasitic regimens (27). Most of them included courses of a combination of pyrimethamine (PYR) and a sulfonamide (sulfadiazine or sulfadoxine [SDX]). However, pharmacokinetic (PK) data for these drugs are scarce, especially for pediatric populations (6,17,23,48), mainly because of the reluctance to pursue PK studies on children. Consequently, many therapeutic agents, such as PYR and SDX, have not been studied adequately in children (24). However, for the past 2 decades, this problem has been addressed by use of the population-based PK approach and the Bayesian method. PK parameter values and their interindividual variability can be determined even when only sparse blood samples are available from a homogeneous or heterogeneous population. Such methodologies can be used even if only one concentration measurement per patient is available (41).Very few studies of the pharmacokinetics of PYR an...

Quantitative Structure – Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution

“…An even higher value of 0.68 L/kg was announced by Wenk et al (37). Similarly, the VD ss value of pyrimethamine in the Obach's database is 0.43 L/kg, while others report for VD ss ranging between 2.12 and 3.06 L/kg (38). Our predicted value of 2.67 L/kg falls in this range.…”

Diagnosis, Treatment, and Prevention of Congenital Toxoplasmosis in the United States

“…The pharmacokinetic data for infants' treatment with pyrimethamine/sulfadoxine (Fansidar) studied by Corvaisier et al, 189 did not establish the concentration of the pyrimethamine/sulfadoxine that is most effi cacious in treating children with CT. They studied 32 infants with CT receiving pyrimethamine/sulfadoxine every 10 days for 1 year, and 101 measurements were collected.…”

Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women

“…These include mean or median t 1/2abs (0.5 to 0.8 h versus 0.93 h in the present study), t 1/2␤ (5.6 to 10.9 days versus 8.4 days), V/F (4 to 20 liters versus combined V ss /F of 11.5 liters), and CL/F (0.02 to 0.08 liters/h versus combined CL/F SDOX ϩ CL M /F of 0.047 liters/h). Previous studies have shown monoexponential (3,9,14,32) or biexponential (19,21,25,34,35) SDOX kinetics. We suggest that our 42-day sampling period, compared to Յ28 days in many previous studies (5,12,14,21,32), facilitated identification of a second compartment.…”

“…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.…”