Population Pharmacokinetics of Pyrimethamine and Sulfadoxine in ...

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2004, p. 3794–3800 0066-4804/04/$08.00⫹0 DOI: 10.1128/AAC.48.10.3794–3800.2004 Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Vol. 48, No. 10

Population Pharmacokinetics of Pyrimethamine and Sulfadoxine in Children Treated for Congenital Toxoplasmosis Ste´phane Corvaisier,1 Bruno Charpiat,1* Cyril Mounier,2 Martine Wallon,3 Gilles Leboucher,1 Mounzer Al Kurdi,3 Jean-Franc¸ois Chaulet,2 and Franc¸ois Peyron3 Department of Pharmacy1 and Department of Parasitology,3 Croix-Rousse Hospital, and Desgenettes Army Teaching Hospital,2 Lyon, France Received 7 October 2003/Returned for modification 14 January 2004/Accepted 27 May 2004

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 hⴚ1, 4.379 liters/kg, 0.00839 hⴚ1, and 5.5 days for PYR and 1.659 hⴚ1, 0.392 liters/kg, 0.00526 hⴚ1, 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 and SDX in pediatric populations have been published (30, 31). More-

over, to the best of our knowledge, the behavior of these two drugs administered simultaneously has never been described for children treated for several months for congenital toxoplasmosis. In France, there is no commercially available oral PYRSDX pediatric combination. Consequently, physicians prescribe one-quarter of a tablet of FANSIDAR (25 mg of PYR plus 500 mg of SDX) per 5 kg of body weight. Parents are asked to crush the tablet and to mix it into a feeding bottle. With these tablets and this dosage regimen, an infant with a body weight of 5 kg receives the same dose as an infant with a body weight of 9 kg. In order to adapt the dose more precisely to body weight, we prepared two types of capsules containing different doses. The aims of this study were to determine population PK parameters of PYR and SDX in children with acquired congenital toxoplasmosis infection who were treated for 1 year, to describe interindividual variability, and to estimate individual PK parameters by using the population-based PK approach and the Bayesian method. In this study, we did not modify the clinical-management procedures, the doses, or the frequency and number of blood samples taken to control for hematological side effects that have been used for several decades. This study was performed under “real-life” conditions. MATERIALS AND METHODS Enrollment of patients and medication. Newborns with proven infection were prescribed a combination of PYR plus sulfadiazine (3 mg/kg of body weight every 3 days and 75 mg/kg daily, respectively) for 3 weeks. This regimen was followed by spiramycin (375,000 U/kg daily) until a body weight of 5 kg was reached. When this body weight was reached, treatment was changed to a PYR-SDX combination (PYR, 1.25 mg/kg; SDX, 25 mg/kg) administered every 10 days (43).

* Corresponding author. Mailing address: Department of Pharmacy, Croix-Rousse Hospital, 103 Grande Rue de la Croix-Rousse, 69317 Lyon Cedex 04, France. Phone: (33) 4-72-07-18-88. Fax: (33) 4-72-0718-94. E-mail: [email protected]. 3794

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The same PYR-SDX treatment was started immediately after diagnosis for children identified as being infected later in life (during their first year after birth), if they weighed at least 5 kg. All children receiving the PYR-SDX combination during the first year of life were considered to be eligible for the PK study. In order to adjust PYR-SDX doses to body weight, two types of capsules containing different doses were prepared: a white capsule for 5 kg of body weight (PYR, 6.25 mg; SDX, 125 mg) and a red capsule for 1 kg of body weight (PYR, 1.25 mg; SDX, 25 mg). Thus, a child weighing 5 kg was prescribed only one white capsule for each dose while a child weighing 9 kg was prescribed one white and four red capsules for each dose. PYR and SDX were supplied by Roche Laboratories (Produits Roche, Neuilly sur Seine, France). Each set of capsules was submitted to a repartition test, a mass test, and analytical controls in accordance with French guidelines (32). Folinic acid (50 mg every week orally) was added to prevent hematological side effects. Patient follow-up. Hematological and serological controls were performed during a visit to the Department of Parasitology, Croix-Rousse Hospital, Lyon, France, just before the start of PYR-SDX therapy. Follow-up visits to the Department of Parasitology were planned 3, 6, 9, and 12 months later. Between these visits, red and white blood cell counts were taken every month in a private laboratory, and the results were transmitted to the Department of Parasitology. At each consultation, PYR-SDX doses were adjusted according to the child’s weight gain and blood was withdrawn for serological and hematological followup. Thus, medication (approximately 10 doses) was given to parents by the pharmacy department for a 3-month period, during which PYR and SDX doses remained unchanged. The dose for each administration was prepared in an individual bag on which the date of administration was written. Parent counseling was carried out by the physician and then by the pharmacist. A dose was prescribed every 10 days, and the parents were asked to open the capsules and to dilute the contents in a half-filled feeding bottle. Advice on correct administration of the treatment was given orally, and a written form describing drug intake was provided. Parents were asked to report the exact day and hour of each administration on a data sheet on which the theoretical dates of drug intake were preprinted. This data sheet was prepared and handed out during pharmacy counseling and was brought back on subsequent visits. Sampling design. The blood-sampling scheme usually used for follow-up of children was not modified, and no additional blood sample to measure drug levels was taken in the 3-month interval between visits, because no direct benefit to the patients was expected from such measures. The ethical issue of blood sampling of asymptomatic children, the locations of their homes (within a radius of 300 km from the hospital), and the obvious uselessness of repeated blood sampling during visits due to the long elimination half-lives (t1/2) of PYR and SDX were taken into account (18, 24, 47). Thus, during the year of treatment, a maximum of five samples per child were planned at the Department of Parasitology and were used to measure PYR-SDX concentrations. In order to enable estimation of the absorption rate constant (Ka) and the volume of distribution in relation to body weight (Vd), one visit to the Department of Parasitology was planned for the morning of the day of drug intake or for the morning of the day after drug intake (42). The local ethics committee approved this study and the sampling design. Analytical procedure. Samples collected for blood cell counts were used to measure plasma drug concentrations. Simultaneous measurements of the concentrations of PYR and SDX in plasma were performed by automated liquidsolid extraction followed by high-performance liquid chromatography with UV detection as described previously (3). The limit of quantification was 0.01 ␮g/ml for PYR and 0.022 ␮g/ml for SDX. Model parameterization and estimation of individual PK parameter values. The nonparametric expectation maximization program (NPEM2) (39) was used to obtain the parameter values and probability densities for a one-compartment model. Parameters determined were the Ka (expressed per hour), the Vd (expressed in liters per kilogram), and the elimination rate constant (Kel; expressed per hour). Initial ranges of potential values of Ka, Vd, and Kel were fixed at 0 to 2 h⫺1, 0 to 10 liters/kg, and 0 to 0.03 h⫺1 for PYR and at 0 to 5 h⫺1, 0 to 2 liters/kg, and 0 to 0.01 h⫺1 for SDX, respectively. The number of grid points used was fixed at 20,011. Iterative parameter estimation was stopped either after a maximum of 1,000 successive iterations or when the difference between two successive values of a convergence criterion was below 0.000001%. For PYR, the polynomial equation for the assay error pattern was 0.0026 ⫺ 0.0075 䡠 C ⫹ 0.0610 䡠 C2, and for SDX, it was 0.0373 䡠 C ⫺ 0.0001 䡠 C2 ⫹ 0.0000003 䡠 C3, where C is measured serum concentration (␮g/ml). Values for the mean, median, standard deviation, coefficient of variation, and 2.5 and 97.5 percentiles were obtained for each parameter. The goodness of fit of the model was assessed by plotting the predicted concentrations against the

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TABLE 1. Characteristics of the population and treatment Characteristic

Mean ⫾ SD

Median

Range

Population At inclusion Age (days) Weight (kg) At the end of therapy Age (days) Weight (kg)

93 ⫾ 51 5.5 ⫾ 0.9

72 5.3

55–293 4.5–9.2

436 ⫾ 89 9.9 ⫾ 1.4

431 9.8

242–760 7.2–13.4

Treatmenta Duration of treatment (days) No. of doses administered No. of blood samples

352 ⫾ 68 35 ⫾ 7 3⫾1

369 37 3

195–477 18–46 2–6

a

Excluding initial therapy with PYR-sulfadiazine and spiramycin.

observed concentrations and by analyzing the standardized prediction error versus observed concentration and versus time elapsed since the beginning of therapy. Bias (the mean of the differences between measured and estimated serum concentrations), precision (the square root of the mean of the squared differences between measured and estimated serum concentrations), the equation of the linear regression of observed versus predicted concentrations, and the coefficient of correlation were calculated. Estimation of individual PK parameter values. For each patient, individual PK parameter values were obtained by using the MAP (maximum a posteriori probability) Bayesian method implemented within the USC*PACK software (version 10.7; Laboratory of Applied Pharmacokinetics, University of Southern California School of Medicine, Los Angeles, 1995 [http://www.lapk.org]). All serum PYR-SDX concentrations measured were fitted by using median values of population PK parameters (12). t1/2 (expressed in hours) was calculated for PYR and SDX, and the percentage of serum levels accurately predicted within a 20% error (SLAP 20) was determined (9). For all patients, the average minimal and maximal concentrations of the drug in serum (Cmin and Cmax, respectively; both measured in micrograms per milliliter) were estimated for each 3-month period.

RESULTS Characteristics of subjects and examination of data. From November 1997 to March 2001, 33 children (20 girls and 13 boys) were enrolled consecutively and completed the study. The file of one foreign child was excluded from this analysis because the parents were unable to fill in the days and hours of medication intake on the report form. Thus, 32 patient files were included in the PK analysis. Population and treatment characteristics are presented in Table 1. Of the 128 data sheets given to parents, 121 were completed correctly and returned (94.5%). A total of 101 concentration measurements were available per drug. According to the protocol described above, 10 children were treated for 21 days with a PYR–sulfadiazine combination, followed by spiramycin, before starting PYRSDX therapy. Treatment with PYR-SDX was interrupted in two children for 31 and 78 days due to moderate neutropenia after 135 and 248 days of treatment, respectively. Both drugs were reintroduced once the white blood cell count became normal, and no further neutropenia was observed. Estimation of population PK parameters. PK parameter values are given in Table 2. Discrete joint probability densities of Vd and Kel are presented in Fig. 1. Bias and precision of estimates of serum drug concentrations using parameter values obtained previously were 0.000846 and 0.037 ␮g/ml for PYR and ⫺2.72 and 14.32 ␮g/ml for SDX, respectively. The plots of observed versus predicted concentrations for PYR and

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ANTIMICROB. AGENTS CHEMOTHER. TABLE 2. PK parameters of PYR and SDX Vd

Ka Drug

PYR SDX a

Kel

⫺1

Mean (h⫺1)

CV (%)a

Median (h⫺1)

0.915 1.659

76 94

0.779 1.226

Value (h ) at percentile 2.5

97.5

0.005 0.013

1.983 4.830

Mean (liters/kg)

CV (%)

Median (liters/kg)

4.380 0.393

61 85

3.000 0.256

Value (liters/kg) at percentile 2.5

97.5

0.380 0.136

9.820 1.416

Mean (h⫺1)

CV (%)

Median (h⫺1)

0.00839 0.00526

62 40

0.00690 0.00560

Value (h⫺1) at percentile 2.5

97.5

0.00234 0.00052

0.02766 0.00902

CV, coefficient of variation, given as a percentage.

SDX are presented in Fig. 2. Correlation coefficients for PYR and SDX were 0.96 and 0.94, respectively (Pearson test; P ⬍ 0.001). Individual PK parameters. The distribution of the t1/2 of PYR-SDX shows an interindividual variability of 1.3 to 20.5 days for PYR (mean, 5.5 ⫾ 4.6 days) and 1.5 to 22.4 days for SDX (mean, 6.6 ⫾ 5.0 days). These values differed by factors close to 16 for PYR and 15 for SDX. There was no correlation between the t1/2 of PYR and SDX (r ⫽ 0.45). For PYR, the SLAP 20 percentage was 69.3%; 31 serum PYR levels measured in 16 children were incorrectly predicted, with an error above 20%. The SLAP 20 percentage for SDX was 75.3%; 25 serum SDX levels measured in 13 children were incorrectly predicted, with an error above 20%. Figure 3 shows plots of standardized prediction errors versus measured concentrations, and versus time elapsed since the start of therapy, for both PYR and SDX. Simulated PYR and SDX concentrationtime curves for six patients after the 10th dose are presented in Fig. 4. The Cmax and Cmin of PYR ranged from 0.15 to 1.20 ␮g/ml (values differed by a factor of 8) and 0.01 to 0.25 ␮g/ml (values differed by a factor of 25), respectively. For SDX, Cmax and Cmin ranged from 50 to 200 ␮g/ml (factor of 4) and 10 to 90 ␮g/ml (factor of 9), respectively. For each drug, the Cmax and Cmin ranges overlapped. A trend of increasing concentration was observed in eight children for PYR and in seven children for SDX.

DISCUSSION PK parameter values. Our goal was to determine the population PK parameters of PYR-SDX in children by using NPEM and to clarify interindividual variability. To date, few studies have been published on the pharmacokinetics of PYRSDX in children with congenital toxoplasmosis (14, 21, 30, 31, 48), and none has reported data on repeated simultaneous administration of both drugs to children (Table 3). No Ka or Vd values in children have been published previously for either PYR or SDX. For the two drugs, the t1/2 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 Vd 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 Vd values in adults ranged from 2.12 to 3.06 liters/kg (1, 13, 15, 44), compared with 4.38 ⫾ 2.68 liters/kg in the children in our study; it was also true for SDX, for which published mean Vd values in adults ranged from 0.13 to 0.15 liters/kg (13, 44) versus 0.39 ⫾ 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. One study performed by Heimann (20) found that the Ka of sulfonamides was lower in infants than in older children. The

FIG. 1. Discrete joint probability densities of the PK parameters Kel and Vd for PYR and SDX.

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FIG. 2. Predicted (Cpred) versus observed (Cobs) concentrations based on Bayesian estimates for PYR (R2 ⫽ 0.92) and SDX (R2 ⫽ 0.88). For both drugs, the line of best fit is not significantly different from the line of identity.

Ka of PYR in our study was lower than values for adults that have been published previously (1, 23, 29), except for the very low Ka reported by Falloon et al. (17). For both drugs, the greatest coefficient of variation was found for the Ka. Two factors may explain such a result. First, one blood sample from only 23 children was collected in the early postintake period (from 0 to 5 h). The lack of blood samples collected soon after administration of the drugs for nine patients may explain the large coefficient of variation for Ka. Second, bottle-feeding conditions are difficult to standardize and control. It is probable that the duration of feeding differed from one occasion to another and among families, and this aspect constitutes a limiting factor in our study. Moreover, we did not assess or record

how parents diluted the content of the capsules. PYR and SDX stability has been studied under various conditions (4, 35, 38), and both drugs were shown to remain stable for several weeks, even at temperatures up to 35°C. However, the PK parameter values that we found are in the same general range as those previously published for adults. The lack of a close relationship between the PK parameters of PYR and SDX is not surprising, because they have different metabolic pathways (8, 40). Consequently, it is not possible to predict the behavior of one drug from that of the other. The discrete joint probability densities (Fig. 1) showed accurately the great diversity of the population studied. For a given value of Kel (i.e., 0.006 h⫺1 for PYR), a wide range of Vd values (1.9 to 10.0 liters/kg) can be observed.

TABLE 3. PK parameter values published for PYR and SDX in children Patients Agea

n

PYR 36 16

e

10 days to 1.5 yr

Duration of treatment

NA

2 to 6 mo 12 mod 1 dose

1

9 yr

1 dose

SDX 16e

NA

1 dose

1

9 yr

1 dose

a

Routeb

Dose (mg/kg)

t1/2 (days)c

Cmax (␮g/ml)c

Oral Oral Oral i.m. Oral

1 per day 1 per 2 days 1.25 1.25 2

2.7 (0.5) 2.7 (0.5) 3.4 (1.3) 5.2 (1.5) 4.6

1.30 (0.50) 0.70 (0.30) 0.53 (0.24) 0.29 (0.05) 0.780

Oral i.m. Oral

25 25 40

NA, not available. i.m., intramuscular. Standard deviations are given in parentheses. d The 2- to 6-month treatment was followed by the 12-month treatment for this group of patients. e Eight patients in oral route group and eight in i.m. route group. b c

4.8 (2.7) 5.2 (1.6) 4.6

79 (22) 115 (30) 193

Reference

31 48 14 48 14

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FIG. 3. Standardized prediction error versus observed concentration (top) and standardized prediction error versus time elapsed since the beginning of therapy (bottom) for PYR and SDX.

Goodness of fit. The goodness of the fit and of prediction were considered to be satisfactory. The data points for predicted concentrations in the population plotted against observed concentrations were, with few exceptions, close. How-

ever, a few samples were greatly underestimated. For both drugs, the bias was very close to zero. Taking into account the range of measured concentrations (0.0 to 0.5 ␮g/ml for PYR and 0 to 200 ␮g/ml for SDX), the precision was very low. The

FIG. 4. Simulated concentration-time curves for PYR and SDX in six patients after the 10th dose.

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error for concentration predictions was above 20% in 31 samples from 16 children for PYR and in 25 samples from 13 children for SDX. The reasons for these observations are not clear, and different hypotheses can be put forward. First, incorrect record keeping or lack of parent compliance with the prescribed regimen are possible: several methods have been used for measuring adherence, although no “gold standard” has been established to date, and we did not find any study that assessed the adherence of the parents of children being treated for congenital toxoplasmosis. Some predictors of poor adherence to medications have been identified; these include poor clinician-patient relationships, active drug and alcohol use, active mental illness, particularly depression, impaired cognitive function, lack of patient education, inability of patients to identify their medications, and lack of reliable access to primary medical care or medication (16, 34). These predictors were not found in the group we studied, except for one family whose data file was excluded because the parents were unable to complete the data sheet. Unidentified interactions with the drugs might have occurred; however, we did not record other drugs prescribed by family physicians. Model misspecification of the absorption phase is another possibility: a more complex model taking into account the duration of feeding may be more suitable. No trend was observed in the plots of the standardized residual versus observed concentrations or versus time elapsed since the start of therapy for PYR and SDX (Fig. 3). A similar finding was obtained for the standardized residual versus time elapsed since the last dose (data not shown). Estimated serum drug concentrations. Estimated peak serum PYR concentrations were lower than those published by McLeod et al. (31); however, the dose of PYR used in that study was greater than that used in this one, and our results are in agreement with those of Edstein et al. (14) and Winstanley et al. (48), who used very similar doses. The serum drug concentrations that we estimated 10 days after drug intake cannot be compared with values measured 24, 48, or 72 h after drug intake (31), although, for SDX, our estimated Cmax values were the same as those of Winstanley (48). It is interesting that, for both drugs, the range of predicted Cmin values based on Bayesian estimates overlapped the range of estimated Cmax values among patients. Because the interindividual variability of PYR-SDX remains great despite the use of doses standardized to body weight, the population PK parameters cannot be used to calculate an a priori starting dose. Comparison of simulated concentrations and in vivo-in vitro model results. Mack and McLeod (28) and Derouin and Chastang (10) studied the antimicrobial effect of the PYRSDX combination on T. gondii in vitro, and both demonstrated a synergistic effect. However, the threshold concentration values of activity were inconsistent. Numerous other studies (11, 19, 25, 37, 46) have examined the antimicrobial effect of PYR alone in experimental toxoplasmosis in vivo or in vitro, and discrepant results have been reported, depending on the experimental conditions. Consequently, we believe that extrapolation of the antimicrobial efficacy of PYR-SDX from in vitro or animal studies to determine a target range of concentrations may be misleading. Consideration must be given to the wide interindividual variability in plasma PYR-SDX levels among patients receiving the same dose regimen. Our observations confirm those of Klinker et al., in a study of adult AIDS

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patients treated for toxoplasmic encephalitis (26), that serum PYR and SDX concentrations are not predictable, even when the dose is standardized to body weight. These results highlight the facts that the results of previously published studies concerning the efficacy and tolerance of PYR and SDX in the treatment of congenital toxoplasmosis need to be reassessed and that pharmacological monitoring of PYR and SDX in children is necessary. The optimal doses and target concentrations in serum still need to be established for PYR and SDX in the treatment of congenital toxoplasmosis. The use of population PK modeling and Bayesian methods is valid in order to perform controlled trials of concentration. Our results might be considered preliminary and could be used in the design of an optimal sampling strategy. A next step will be to identify covariates that could influence the behavior of both drugs and to study the relationship between PK parameters and the pharmacodynamics of both drugs. Long-term follow-up will be necessary to determine the relationship, if any, between the individual PK parameters, the intensity of drug exposure, and the late onset of sequelae. REFERENCES 1. Ahmad, R. A., and H. J. Rogers. 1980. Pharmacokinetics and protein binding interactions of dapsone and pyrimethamine. Br. J. Clin. Pharmacol. 10:519– 524. 2. Akintonwa, A., and O. Obodozie. 1991. Effect of activated charcoal on the disposition of sulphadoxine. Arch. Int. Pharmacodyn. Ther. 309:185–192. 3. Astier, H., C. Renard, V. Cheminel, O. Soares, C. Mounier, F. Peyron, and J. F. Chaulet. 1997. Simultaneous determination of pyrimethamine and sulphadoxine in human plasma by high-performance liquid chromatography after automated liquid-solid extraction. J. Chromatogr. B 698:217–223. 4. Bergqvist, Y., E. Hjelm, and L. Rombo. 1987. Sulfadoxine assay using capillary blood samples dried on filter paper—suitable for monitoring of blood concentrations in the field. Ther. Drug Monit. 9:203–207. 5. Bourget, P., A. Lesne-Hulin, F. Forestier, V. Desmaris, and E. Dulac. 1996. Pre´vention de la toxoplasmose conge´nitale par la spiramycine: inte´reˆt et limite du dosage dans le liquide amniotique. Therapie 51:685–687. 6. Bustos, D. G., J. E. Lazaro, F. Gay, A. Pottier, C. J. Laracas, B. Traore, and B. Diquet. 2002. Pharmacokinetics of sequential and simultaneous treatment with the combination chloroquine and sulfadoxine-pyrimethamine in acute uncomplicated Plasmodium falciparum malaria in Philippines. Trop. Med. Int. Health 7:584–591. 7. Butler, D. R., R. J. Kuhn, and M. H. Chandler. 1994. Pharmacokinetics of anti-infective agents in paediatric patients. Clin. Pharmacokinet. 26:374–395. 8. Cavallito, J. C., C. A. Nichol, W. D. Brenckman, R. L. Deangelis, D. R. Stickney, W. S. Simmons, and C. W. Sigel. 1978. Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man. Drug Metab. Dispos. 6:329–337. 9. Charpiat, B., and V. Bre´ant. 1994. Another suggestion for measuring predictive performance for aminoglycoside therapy. Intern. J. Bio-Med. Comput. 36:161–162. 10. Derouin, F., and C. Chastang. 1988. Enzyme immunoassay to assess effect of antimicrobial agents on Toxoplasma gondii in tissue culture. Antimicrob. Agents Chemother. 32:303–307. 11. Derouin, F., and M. Santillana-Hayat. 2000. Anti-toxoplasma activities of antiretroviral drugs and interactions with pyrimethamine and sulfadiazine in vitro. Antimicrob. Agents Chemother. 44:2575–2577. 12. Dodge, W., R. W. Jelliffe, C. J. Richardson, R. Bellanger, J. Hokanson, and W. Snodgrass. 1993. Population pharmacokinetic models: measures of central tendency. Drug Investig. 5:206–211. 13. Edstein, M. D. 1987. Pharmacokinetics of sulfadoxine and pyrimethamine after Fansidar administration in man. Chemotherapy 33:229–233. 14. Edstein, M. D., I. D. Lika, T. Chongsuphajaisiddhi, A. Sabchareon, and H. K. Webster. 1991. Quantitation of Fansimef components (mefloquine ⫹ sulfadoxine ⫹ pyrimethamine) in human plasma by two high-performance liquid chromatographic methods. Ther. Drug Monit. 13:146–151. 15. Edstein, M. D., K. H. Rieckmann, and J. R. Veenendaal. 1990. Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man. Br. J. Clin. Pharmacol. 30:259–265. 16. Escobar, I., M. Campo, J. Martin, C. Fernandez-Shaw, F. Pulido, and R. Rubio. 2003. Factors affecting patient adherence to highly active antiretroviral therapy. Ann. Pharmacother. 37:775–781. 17. Falloon, J., J. Lavelle, D. Ogata-Arakaki, A. Byrne, A. Graziani, A. Morgan,

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