Single dose kinetic study of the triple combination mefloquine/sulphadoxine/pyrimethamine (Fansimef) in healthy male volunteers.

Mansor, Sharif Mahsufi; Navaratnam, V.; Mohamad, M.; Hussein, Shamsuddin; Kumar, Ashok; Jamaludin, A; Wernsdorfer, W. H.

doi:10.1111/j.1365-2125.1989.tb05381.x

Cited by 34 publications

(24 citation statements)

References 14 publications

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“…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%

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

Corvaisier¹,

Charpiat²,

Mounier

et al. 2004

Antimicrob Agents Chemother

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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...

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Section: Discussionsupporting

confidence: 75%

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

Corvaisier¹,

Charpiat²,

Mounier

et al. 2004

Antimicrob Agents Chemother

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“…A recent study indicated that a similar HPLC assay could also be used to measure pyrimethamine levels in infant plasma but did not report any values for infant plasma that had been collected (22). As noted above, the disposition of pyrimethamine in the infants we studied appears to be in the range in adults noted by others (2,7,12,19,20,22). For example, serum pyrimethamine levels in immunologically normal adults while taking a 25-mg (0.3-mg/kg) daily dose (measured with our HPLC assay) ranged from 0.9 to 1.7 ,ug/ml.…”

Section: Discussionmentioning

confidence: 50%

“…For example, serum pyrimethamine levels in immunologically normal adults while taking a 25-mg (0.3-mg/kg) daily dose (measured with our HPLC assay) ranged from 0.9 to 1.7 ,ug/ml. Time to peak levels in Malaysian adult volunteers was found to be 3.3 + 1.98 h and half-life was 114 + 42 h (12), and half-lives in adults have been reported to range from 23 to 175 h (22). As noted above, in a study of human immunodeficiency virusinfected patients, levels with 25-to 75-mg doses for adults (weight not specified) ranged from 260 to 4,471 ng/ml (20).…”

Section: Discussionmentioning

confidence: 99%

Levels of pyrimethamine in sera and cerebrospinal and ventricular fluids from infants treated for congenital toxoplasmosis. Toxoplasmosis Study Group

McLeod¹,

Mack²,

Foss³

et al. 1992

Antimicrob Agents Chemother

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Pyrimethamine levels in sera, cerebrospinal fluid(CSF), and ventricular fluid were measured by using reversed-phase high-pressure liquid chromatography. The specimens were from 37 infants receiving pyrimethamine for treatment of suspect or proven congenital toxoplasmosis. Pyrimethamine half-life in serum was 64 ± 12 h when determined by study of terminal-phase kinetics of samples obtained from nine babies. This half-life was significantly different (P = 0.008) from the pyrimethamine half-life (33 ± 12 h) determined by terminal-phase kinetics for two babies of the same age taking phenobarbital. Serum pyrimethamine levels at various intervals after dosages of pyrimethamine were also lower for infants receiving phenobarbital. Levels measured in sera from babies taking the same dose of pyrimethamine throughout their first year of life did not appear to vary significantly over time or at different ages (P > 0.05). Mean + standard deviation serum levels 4 h after a pyrimethamine dose were 1.297 ± 0.54 pg/ml for babies taking 1 mg of pyrimethamine per kg of body weight daily and 0.7 + 0.26 ,ug/ml for babies taking 1 mg/kg each Monday, Wednesday, and Friday. Levels in CSF were approximately 10 to 25% of concomitant levels in serum. Serum folate levels for infants who took 0.64 to 1.7 mg leukovorin per kg ranged from 33 to 663 ng/ml. To determine whether the levels of pyrimethamine in serum and CSF of treated infants were in a range that affected the most virulent, rapidly replicating, and standard laboratory strain of Toxoplasma gondii, effects of various concentrations of pyrimethamine and sulfadiazine on replication of T. gondii in vitro were assessed. The levels of the antimicrobial agents effective in vitro were in the range of levels of pyrimethamine achieved in sera and CSF. Although folinic acid could inhibit the therapeutic effect of pyrimethamine and sulfadiazine in vitro, inhibition was noted only at levels (.4,800 ng/ml) that were considerably higher than the folate levels found in the treated infants' sera.Pyrimethamine is a critical part of therapy for babies with congenital toxoplasmosis (15). It is also important in therapy of infants with human immunodeficiency virus infection who also have toxoplasmic encephalitis (16). Data concerning pharmacokinetics of this agent in infants and children are greatly needed, as there are no data available to guide rational selection of pyrimethamine dosage for such patients. MATERIALS AND METHODSPatients and sampling strategy. Sera were obtained from infants between the ages of 10 days and 1.5 years. The infants were receiving pyrimethamine for treatment of suspect or definite congenital toxoplasmosis. These sera were obtained in accordance with National Institutes of Health guidelines concerning human subjects, which includes informed consent from parents and guardians. In some instances, when cerebrospinal fluid (CSF) or cerebral ventricular fluid were available, these samples were also studied. In the feasibility phase of this study a recommendation was * Correspond...

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“…Despite a prohibitive price making their deployment difficult, artemisinin-based combination therapies (ACTs) are the best antimalarial treatments available nowadays and are recommended by WHO since 2001 (Mutabingwa, 2005). MEF was additive in both studies but it is not an optimal candidate because persistence of subinhibitory concentrations for long periods (elimination t 1/2 , 2 weeks) (Karbwang et al, 1988;Mansor et al, 1989). CQ remains one of the cheapest antimalarial easily accessible in developing countries.…”

Section: Discussionmentioning

confidence: 99%

Blood schizontocidal activity of methylene blue in combination with antimalarials againstPlasmodium falciparum

et al. 2007

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Summary :Methylene blue (MB) is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50 % of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC) method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy. Résumé

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Single dose kinetic study of the triple combination mefloquine/sulphadoxine/pyrimethamine (Fansimef) in healthy male volunteers.

Cited by 34 publications

References 14 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

Levels of pyrimethamine in sera and cerebrospinal and ventricular fluids from infants treated for congenital toxoplasmosis. Toxoplasmosis Study Group

Blood schizontocidal activity of methylene blue in combination with antimalarials againstPlasmodium falciparum

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