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Pharmacokinetics of Buspirone in Autistic Children

From the Department of Pharmacy Practice (Dr Edwards), the Carman and Ann Adams Department of Pediatrics (Dr Edwards, Dr D. Chugani, Dr H. Chugani, Dr Aranda), the Department of Neurology (Dr H. Chugani), and the Department of Radiology (Dr D. Chugani, Dr. H. Chugani), Wayne State University, Detroit, Michigan; the Division of Clinical Pharmacology (Dr Edwards, Dr D. Chugani, Ms Chehab, Dr Aranda), PET Center (Dr D. Chugani, Dr H. Chugani), and the Department of Pharmacy Services (Ms Malian), Children's Hospital of Michigan and the NICHD-Pediatric Pharmacology Research Unit Network, Detroit, Michigan.

Address for reprints: David J. Edwards, PharmD, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201; e-mail: dje{at}wayne.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Buspirone is used to treat generalized anxiety disorder in children and may be useful in developmental disorders in which brain serotonin synthesis is altered. Autistic children (13 boys, 7 girls) were given a single oral dose of 2.5 mg (2-3 years) or 5.0 mg (4-6 years). Blood was collected for 8 hours, and plasma was assayed for buspirone and its metabolite 1-pyrimidinylpiperazine (1-PP). The peak concentration of buspirone averaged 1141 ± 748 pg/mL with a time to maximum concentration of 0.8 hours. Half-life was 1.6 ± 0.3 hours. Peak concentrations of 1-PP were 4.5-fold higher than for buspirone. Girls had higher peak concentrations (1876 vs 746 pg/mL) for buspirone and a lower peak 1-PP/buspirone concentration ratio. These results suggest that buspirone is rapidly absorbed and eliminated in young children with extensive metabolism to 1-PP. Plasma concentrations with 2.5- to 5.0-mg doses were similar to those observed in older children receiving 7.5- to 15-mg doses.

Key Words: Buspirone • pediatrics • pharmacokinetics • gender • autism

In adults and older children, buspirone disposition is characterized by rapid absorption, low oral bioavailability due to extensive first-pass metabolism by CYP3A4 and a short half-life of 2 to 4 hours. Peak concentrations of the parent compound are highly variable and several-fold lower that those of the metabolite 1-pyrimidinylpiperazine (1-PP).^4-7 The pharmacokinetics of buspirone have not been reported in children under the age of 6 years. For many drugs, including CYP3A4 substrates such as midazolam and cyclosporine, clearance in young children is higher than in adolescents and adults when adjusted for weight, and the half-life tends to be shorter.^8,9 In addition, there are little data in this population on the disposition of substrates that undergo extensive first-pass metabolism. The objective of this investigation was to study the pharmacokinetics of buspirone in autistic children between the ages of 2 and 6 years to assess the influence of development on disposition as well as to develop initial dosing guidelines for use in young children with autism and other disorders.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Design
This was a prospective, single-dose, single-site study (Children's Hospital of Michigan, Detroit, Michigan) in which the pharmacokinetics of buspirone was examined in autistic children. Children (male or female) were eligible to participate if they were between 2 and 6 years of age and had a diagnosis of autism based on the Autism Diagnostic Interview–Revised.¹⁰ Subjects were excluded if they had clinical or laboratory evidence of renal or hepatic disease (alanine aminotransferase, serum gamma glutamyl transferase greater than 2 x normal value, serum creatinine greater than 120 mmol) or were receiving any substances known to alter CYP3A4 activity including ketoconazole, itraconazole, grape-fruit juice, erythromycin, clarithromycin, cimetidine, verapamil, diltiazem, rifampin, phenytoin, phenobarbital, or carbamazepine within the previous 3 months. Written informed consent was obtained from parents or legal guardians, and the study was approved by the Wayne State University Human Investigation Committee.

Children aged 2 to <4 years were given a dose of 2.5 mg, whereas those between the ages of 4 and 6 received 5.0 mg. Buspirone hydrochloride (United State Pharmacopeia) was purchased from Spectrum Chemicals and Laboratory Products (New Brunswick, NJ) and compounded in a liquid formulation at a concentration of 2.5 mg/mL in Orasweet (Oramedix Inc, Lancaster, Calif). The potency and stability of this solution was confirmed using a stability-indicating high-performance liquid chromatographic assay developed in our laboratory. Solutions were assayed at 1, 2, 3, 7, 14, and 30 days after storage at both room temperature and 4°C. There was no loss of potency during this time frame. Solution for use in the study was assigned a 30-day expiry date and refrigerated before use.

On the day of the study, buspirone was administered with apple sauce (1 tablespoon), water, or apple juice (100 mL) between 1 and 3 hours after an age-appropriate breakfast. Venous blood samples (1 mL) were collected immediately before and 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, and 8.0 hours after drug administration. Subjects were monitored for adverse events throughout the blood collection period. At the completion of the sampling period, vital signs were measured, and blood and urine were collected for urinalysis, hematology, and blood chemistry.

The concentration of buspirone and 1-PP in plasma was measured using liquid chromatographymass spectrometry (Applied Biosystems/MDS Sciex 4000 Q-TRAP triple quadrupole mass spectrometer; Foster City, Calif). Deuterated analogs (D8-labelled) of buspirone and 1-PP were used as internal standards. Samples were prepared for injection using solid phase extraction (Oasis 1 cc cartridges; Waters Corp, Milford, Mass). The mobile phase consisted of an 80:20 mixture of methanol and 10 mM ammonium acetate in water pumped at a flow rate of 0.5 mL/min through the analytical column (Thermo PFP 2.1 mm x 5 cm, 5µ d_P, Thermo Electron Corp, Madison, Wis). The limit of detection of the method was 50 pg/mL for buspirone and 200 pg/mL for 1-PP. Accuracy was within 4% of the nominal concentration for all buspirone standards and controls. The coefficient of variation was 4.2% and 7.1% for buspirone (4000 pg/mL) and 1-PP (10 000 pg/mL), respectively.

Pharmacokinetic Analysis
The pharmacokinetic parameters for buspirone and 1-PP were determined using standard noncompartmental techniques. For both compounds, maximum concentration (C_max) and time to C_max (t_max) were obtained directly from the plasma concentration-time curves for individual subjects. Elimination rate constant (k) was estimated by linear regression analysis of the terminal portion of the plasma concentration-time profile; half-life was calculated by dividing 0.693 by k. Area under the plasma concentration-time curve during the sampling period (AUC_t) was assessed using the linear trapezoidal rule. The area extrapolated to infinite time (AUC_I) was calculated as AUC_t + C_t /k, where C_t was the last measurable plasma concentration. The administered dose was divided by AUC_I to obtain the oral clearance of buspirone (Cl/F). The ratio of metabolite to parent compound (1-PP/buspirone) was determined for both C_max and AUC_I.

Statistical Analysis
Descriptive statistics (mean, standard deviation, coefficient of variation) were calculated for all pharmacokinetic parameters. The effect of dose, race, and gender on the disposition of buspirone and 1-PP was assessed by analysis of variance using SYSTAT 5.0 for Windows (SYSTAT Inc, Evanston, Ill). In addition, correlation analysis was used to examine relationships between demographic factors (age in months, weight-adjusted dose) and pharmacokinetic parameters. A value of = .05 was used for statistical significance.

	RESULTS

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Twenty-four subjects were initially enrolled, and 20 successfully completed the study and were included in the data analysis. For 3 individuals, consent was withdrawn after screening but before receiving any medication. In addition, a fourth subject appeared to spit up the dose and had undetectable plasma concentrations within 1.5 hours of drug administration. The demographic characteristics of the study population are listed in Table I. Subjects receiving the 2.5-mg dose (n = 11) averaged 41 months in age, whereas the 5.0-mg dose was administered to 9 subjects with an average age of 55 months. There were 13 boys and 7 girls in the study with a racial distribution of 12 whites, 6 black/African Americans, and 2 Asians.

The mean plasma concentration-time profile for buspirone and 1-PP is illustrated in Figure 1, and the pharmacokinetic parameters for all subjects are listed in Table II. Buspirone concentrations were above the limit of detection in 15 of 20 subjects at 6 hours and 12 of 20 subjects at 8 hours. Peak concentrations of buspirone were 957 and 1366 pg/mL with the 2.5- and 5.0-mg doses, respectively. However, there were no dose-related statistically significant differences in buspirone half-life (1.66 vs 1.55 hours), Cl/F (79.2 vs 98.3 L/kg/h), the metabolite/parent ratio of peak concentration (4.4 vs 4.6), or AUC (12.5 vs 11.8). No statistically significant correlation was observed between the mg/kg dose and any of the measured pharmacokinetic parameters. In addition, no significant relationship was observed between subject age (months) and dose-corrected C_max, AUC_I, half-life, or metabolite/parent ratio. Race had no statistically significant influence on any pharmacokinetic parameter, but several differences related to gender were noted. As illustrated in Figure 2, peak plasma concentrations for buspirone were substantially elevated in female subjects (1876 vs 746 pg/mL, P < .05), an increase that greatly exceeded the difference in dose between the groups (0.21 vs 0.18 mg/kg for female subjects and male subjects, respectively). A significant gender difference was also observed in buspirone AUC_I, Cl/F, and C_max ratio (Table III). The mean buspirone half-life was 1.6 hours in male and female subjects.

View larger version (10K): [in this window] [in a new window]   Figure 1. Mean (+SD) concentrations of buspirone and 1-pyrimidinylpiperazine (1-PP) in autistic children.

View larger version (7K): [in this window] [in a new window]   Figure 2. Box plot of maximum concentration (Cmax) and area under the plasma concentration-time curve ratio (AUC, 1-pyrimidinylpiperazine [1-PP]/buspirone) in male and female autistic children.

One subject (subject 9) experienced mild diarrhea after taking the study drug. Otherwise, there were no clinically significant adverse events related to buspirone administration in this study.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Buspirone is used to treat generalized anxiety disorder in children.¹ In addition, conditions such as autism and pervasive development disorder may be related to alterations in brain serotonin synthesis, suggesting that drugs with serotonin agonist properties might have value in treatment.^2,3 These disorders occur in young children, and pharmacologic intervention is likely to be more effective if initiated during critical periods of brain development regulated by serotonin.¹¹ The disposition of buspirone has not been previously described in patients less than 6 years of age, making the selection of a dose for clinical trials in this population difficult. In adults and older children, buspirone is rapidly and completely absorbed after oral administration. Absolute bioavailability is less than 5% because of extensive first-pass extraction resulting in highly variable peak concentrations less than 5 ng/mL with standard doses.^4-6 Concentrations of 1-PP exceed those of the parent compound by several-fold. Buspirone has a short half-life, averaging 2 to 4 hours in adults,⁴ and similar values have been reported in children (6-12 years) and adolescents with anxiety disorder.⁷ Because CYP3A4 appears to be responsible for the metabolism of this drug, inducers or inhibitors of this enzyme can substantially alter systemic exposure to buspirone. Five- to 10-fold increases in peak plasma concentrations have been observed when buspirone is given with CYP3A4 inhibitors such as verapamil, diltiazem, itraconazole, or erythromycin, whereas the CYP3A4 inducer rifampin reduces buspirone concentrations by 80% to 90%.^4,12,13 The observation that grapefruit juice results in a 9-fold increase in the AUC of buspirone¹⁴ suggests that much of the first-pass metabolism is mediated by CYP3A4 in the enterocyte because components of grapefruit juice act as selective inhibitors of this enzyme in the gut wall.¹⁵ Relatively few drugs exhibit extensive gut wall metabolism, and there are limited pharmacokinetic data in young children for any drug with this property.

In adults, a typical buspirone dose of 15 mg is roughly equivalent to 0.2 mg/kg. The doses of 2.5 and 5.0 mg for children aged 2 to 4 years and 4 to 6 years, respectively, were expected to provide similar mg/kg doses to adults, given average weights for children in this age range. The mean administered dose of 0.19 mg/kg was consistent with expectations, but the range of doses on a mg/kg basis varied approximately 3-fold (0.11-0.31 mg/kg). In retrospect, the children who received 5.0 mg were only 14 months older and 3 kg heavier than those who received 2.5 mg, which resulted in the older children receiving a dose of 0.25 mg/kg compared with 0.14 mg/kg for the 2- to 4-year-old children. Despite these differences between the groups in the administered mg/kg dose, parameters such as Cl/F, elimination half-life, and metabolite/parent compound ratios did not exhibit any evidence of dose dependence.

Salazar et al⁷ studied the pharmacokinetics of buspirone under steady-state conditions after the administration of doses ranging from 7.5 to 15 mg twice daily to children with a mean age of 9 years. Peak concentrations of 0.67 and 1.96 ng/mL were observed with the 7.5- and 15-mg doses, respectively, whereas corresponding values for AUC were 1.48 and 4.80 ng·h/mL. Plasma concentrations of buspirone in this study were comparable. Peak concentrations averaged 0.96 ng/mL with the 2.5-mg dose and 1.37 ng/mL after administration of 5.0 mg (Table II). The AUC for buspirone with 2.5-mg and 5.0-mg doses was also in the middle of the range observed in children given 7.5- and 15.0-mg doses. The half-life of 1.61 hours observed in this study is similar to the average values for half-life between 1.99 and 3.13 hours reported by Salazar et al⁷ in older children.

Extensive metabolism of buspirone to 1-PP has been observed in adults and older children, and the results of this study indicate that 1-PP is also formed in substantial quantity in young children. The multiple-dose study design used by Salazar et al⁷ could potentially result in accumulation of metabolite, making a direct comparison with the results of this single-dose study difficult. Nonetheless, both studies found that metabolite concentrations were several-fold higher than those of the parent compound with an elimination half-life of 3 to 4 hours for 1-PP.

An unexpected finding in this study was the observation of a statistically significant difference in several parameters related to gender (Table III). Buspirone peak concentrations and AUC in female subjects were more than double those observed in male subjects, even though the dose in female subjects was only 17% higher (0.21 vs 0.18 mg/kg). This finding was accompanied by metabolite/parent concentration ratios in female subjects that were about half of the values observed in male subjects. Given that the elimination half-life of buspirone was identical (1.6 hours) in both groups, the most logical explanation for these findings is that female subjects had higher bioavailability because of less extensive first-pass metabolism of buspirone. This finding would also imply lower enterocyte CYP3A4 activity in young girls because the enterocyte appears to be the primary site of buspirone first-pass metabolism. The effect of gender on the disposition of CYP3A4 substrates in adults has been the subject of a number of investigations with conflicting results. The oral bioavailability of verapamil has been reported to be increased in women.^16,17 However, Gorski et al¹⁸ did not observe an increase in either oral bioavailability or availability across the gut wall of midazolam in adult females. Paine et al¹⁹ obtained duodenal biopsies from healthy men (n = 46) and women (n = 45) and examined the expression of CYP3A4. Mean CYP3A4 expression values were 1.09 and 1.10 in men and women, respectively. In the case of buspirone, no differences related to gender were found in C_max or AUC after administration of the extended-release product.²⁰ Further study is needed to determine if the observation of increased buspirone bioavailability in prepubertal females is a true gender effect or an artifact related to some other unidentified factor in the female population with autism in this study.

The results of this study suggest that 2.5- and 5.0-mg doses of buspirone administered to children between the ages of 2 and 6 years will result in plasma concentrations of buspirone and 1-PP that are similar to concentrations observed in older children receiving 7.5 to 15 mg. Assuming that there are no significant differences in the distribution of drug or any active metabolites to the site of action and that the concentration-response relationship is not age-dependent, buspirone doses of 2.5 to 5.0 mg or 0.2 mg/kg should be appropriate for initiating treatment in young children. Further investigation of the effect of gender on buspirone disposition in young children is needed.

DOI: 10.1177/0091270006286903

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

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