Pharmacokinetics and protein binding interactions of dapsone and pyrimethamine.

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...

Section: Discussionsupporting

confidence: 75%

Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Corvaisier¹,

Charpiat²,

Mounier

et al. 2004

“…The mean elimination half-life of pyrimethamine was approximately 140 h, and this figure is in broad agreement with estimates made after oral dosing, which have ranged from 35 to 175 h (1,5,6,13). The present estimates for AUC 0-ϱ (and derived parameters, such as clearance and volume of distribution) vary markedly from those after oral dosing.…”

supporting

confidence: 76%

Disposition of Intravenous Pyrimethamine in Healthy Volunteers

Almond

Szwandt

Edwards

et al. 2000

A proportion of patients with AIDS and toxoplasmic encephalitis (TE) sustain low plasma pyrimethamine concentrations during oral treatment, possibly because of incomplete and variable bioavailability. We wanted to develop a safe, practicable intravenous (i.v.) formulation of pyrimethamine and characterize its disposition in healthy volunteers. A neutral, aqueous, sterile solution of pyrimethamine was produced and presented in sealed glass ampoules. Pyrimethamine (1 mg/kg) was given to eight healthy male volunteers by i.v. infusion over 2 h, and blood was sampled over a 2 week period. Pyrimethamine levels in plasma were measured by highperformance liquid chromatography. The drug was well tolerated by all volunteers, and there were no changes in vital signs, electrocardiogram, hematology, or biochemical parameters. The maximum pyrimethamine concentration of 2,089 ؎ 565 ng ml ؊1 (mean ؎ standard deviation) was achieved shortly after the end of the infusion; thereafter, concentrations declined in a log-linear manner, with a half-life of 140 ؎ 31 h.

“…Prior to Metroka and colleagues implicating didanosine's buffers as decreasing dapsone bioavailability, no drug interactions with this agent during absorption were reported; rather, effects of other drugs on dapsone elimination and protein binding have been established (1). Because gastric pH was not found to have an effect on the absorption of dapsone, it could theoretically be extrapolated that other drugs which increase gastric pH, such as didanosine, H2 antagonists, and omeprazole, also do not alter the absorption of dapsone.…”

mentioning

confidence: 99%

Evaluation of effects of altered gastric pH on absorption of dapsone in healthy volunteers

Breen

Brocavich

Etzel

et al. 1994

A prospective, randomized, crossover study was performed with seven healthy volunteers to address the effect of increased gastric pH on dapsone absorption. Subjects were randomized to receive a single 100-mg dose of dapsone or a single 100-mg dose of dapsone in addition to 30 ml of a high potency antacid 1 h before dapsone administration and hourly thereafter for a total of 10 doses. Dapsone concentrations in serum were measured periodically for 48 h. No statistical differences between the two regimens were noted when mean dapsone maximal initial concentrations, times to peak, and areas under the curve were compared. These data suggest that an increase in gastric pH has little or no effect on the absorption of dapsone in healthy subjects.Dapsone is frequently employed in the prophylaxis and treatment of Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus (4, 13). Metroka et al. reported that dapsone's efficacy was significantly reduced in patients who received concomitant didanosine therapy. The mechanism postulated for this interaction was that the buffering agents in didanosine elevated gastric pH, resulting in decreased dapsone absorption (12). This hypothesis was based on in vitro findings that have shown dapsone to be insoluble in a neutral pH environment and completely soluble in an acidic environment (17). Since this report, the effect of increased gastric pH on dapsone absorption has been debated (7,8).The speculation that dapsone may require an acidic environment for absorption is potentially significant, especially in AIDS patients, since achlorhydria has been described in this population (9-11). However, clinical studies to evaluate the absorption characteristics of dapsone in the presence of elevated gastric pH have not yet been performed. As such, this prospective, crossover study was performed with healthy volunteers to evaluate the effect of increased gastric pH via concomitant antacid administration on dapsone absorption.The study protocol was approved by the Institutional Review Boards at Nassau County Medical Center and St. John's University. Healthy volunteers over 18 years old were enrolled after giving informed written consent. The study subjects underwent an initial physical exam as well as a routine serum chemistry work-up which included routine laboratory monitoring. Additionally, their glucose-6-phosphate dehydrogenase level was evaluated. Human chorionic gonadotropin levels in blood and urine were evaluated prior to the first and second stages of study for all female subjects. Subjects were excluded from the study if they (i) were taking any scheduled medications; (ii) had an estimated creatinine clearance of less than 30 ml/min as determined by the equation of Cockcroft and Gault (5); (iii) had liver impairment, which was defined biochemically by liver function test results reported to be greater than two times higher than laboratory normal values or by a history of end-stage liver disease and/or cirrhosis; (iv) had a known