Multiple‐dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man.

Edstein, Michael D.; Rieckmann, Karl H.; Veenendaal, J.R.

doi:10.1111/j.1365-2125.1990.tb03773.x

Cited by 21 publications

(12 citation statements)

References 18 publications

(17 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…No K a or V d values in children have been published previously for either PYR or SDX. For the two drugs, the t 1/2 were in the same general range as those published previously for children (14,17,48) and for adults (1,2,5,6,13,15,17,21,22,23,29,33,44,45), and our results showed wide interindividual variability of both drugs in children. In a review, Butler et al (7) indicated that the V d for many drugs was greater in children than in adults and that elimination may be altered in children compared with adults.…”

Section: Discussionsupporting

confidence: 75%

“…In a review, Butler et al (7) indicated that the V d for many drugs was greater in children than in adults and that elimination may be altered in children compared with adults. This was the case for PYR, for which published mean V d values in adults ranged from 2.12 to 3.06 liters/kg (1,13,15,44), compared with 4.38 Ϯ 2.68 liters/kg in the children in our study; it was also true for SDX, for which published mean V d values in adults ranged from 0.13 to 0.15 liters/kg (13, 44) versus 0.39 Ϯ 0.33 liter/kg in children. No data comparing the PK behavior of sulfonamides in the absorption phase according to age (from newborn to adult) were found.…”

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

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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

Corvaisier¹,

Charpiat²,

Mounier

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…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

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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.

show abstract

“…As expected on the basis of the half-lives of 23-25 hours for dapsone and 80-105 hours for pyrimethamine [28,29], serum concentrations of dapsone decreased considerably throughout the weekly dosing interval, whereas pyrimethamine levels remained relatively stable in most of the sera examined [20]. Maintenance of high serum levels may be less important for prophylaxis than for cure, as shown by the experience with weekly doses of dapsone [18] and that with intermittent doses of trimethoprim-sulfamethoxazole [6,24,30]: both regimens prevented PCP, although the dosing interval exceeded the half-life of the individual compounds severalfold.…”

Section: Discussionmentioning

confidence: 64%

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Opravil

Hirschel

Lazzarin

et al. 1995

Clinical Infectious Diseases

View full text Add to dashboard Cite

To evaluate combined prophylaxis for Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis, 533 patients with symptomatic human immunodeficiency virus infection and/ or CD4 lymphocyte counts of <200/AL were randomized to receive dapsone/pyrimethamine (200/75 mg once weekly) or aerosolized pentamidine (300 mg every 4 weeks). The median CD4 lymphocyte count was 110/AL; 47.5% were seropositive for toxoplasma antibodies. The median duration of follow-up was 483 days. In the intent-to-treat analysis, 12 cases of PCP and 14 of toxoplasmic encephalitis occurred in the dapsone/pyrimethamine group and 13 and 20 cases, respectively, in the aerosolized pentamidine group (adjusted relative risk for toxoplasmosis, 0.56; P = .10). However, only two of the 14 cases of toxoplasmic encephalitis in the dapsone/ pyrimethamine group developed during actual treatment. The mortality among the two groups was similar. Dapsone/pyrimethamine was not tolerated by 30% of participants. A subanalysis of 240 matched, tolerant patients yielded a relative risk for toxoplasmosis of 0.21 (P = .014), a result favoring the use of dapsone/pyrimethamine. Dapsone/pyrimethamine was as effective as aerosolized pentamidine as prophylaxis for PCP and significantly reduced the incidence of toxoplasmic encephalitis among those participants who tolerated it.Prophylaxis for opportunistic infections has had a strong impact on the management of immunosuppressed human immunodeficiency virus (HIV)-infected patients in recent years, and epidemiological data indicate that Pneumocystis carinii pneumonia (PCP) has become less frequent as a consequence of prevention [1]. Aerosolized pentamidine became available in Switzerland in 1987 and was subsequently proven effective for both primary and secondary prophylaxis for PCP in controlled trials [2,3]. Among systemic prophylactic agents, trimethoprim-sulfamethoxazole became widely used [4] and was later shown to be more effective but also more toxic than aerosolized pentamidine [5,6] nations, such as dapsone and trimethoprim [7] or pyrimethamine and sulfadiazine [8], have been used for treatment of PCP before, but sparse data exist concerning their prophylactic efficacy [9]. Only recently, the prophylactic efficacy of the combination of dapsone and pyrimethamine against PCP and toxoplasmosis was demonstrated [ 10].Since in >95% of all AIDS patients with toxoplasmic encephalitis there is serological evidence of previous infection with Toxoplasma gondii [10][11][12][13], reactivation of a latent infection is the principal pathogenetic step in the development of toxoplasmic encephalitis during immunodeficiency. Considering the increasing frequency of toxoplasmic encephalitis among AIDS-defining opportunistic infections [ 1] and the 50% seroprevalence of toxoplasma antibodies in Switzerland [14], primary prophylaxis for toxoplasmic encephalitis seems desirable and clinically important, at least for seropositive patients.The sequential inhibition of dihydrofolate reductase by pyrimethamine and of dihydropteroate sy...

show abstract

Multiple‐dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man.

Cited by 21 publications

References 18 publications

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

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

Disposition of Intravenous Pyrimethamine in Healthy Volunteers

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Contact Info

Product

Resources

About