Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation

Hiroyoshi Nakamura, Takeyuki Sato, Kenji Okada, Go Miura, Noritaka Ariyoshi, Kazuyoshi Nakazawa, Mitsukazu Kitada

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15 Citations (Scopus)

Abstract

The objectives of this study were to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of busulfan in Japanese pediatric patients who received high-dose oral busulfan as a conditioning regimen before hematopoietic stem cell transplantation. Population analysis was performed using retrospective therapeutic drug monitoring data (including test dose data) from 103 children. Their ages ranged from 2 months to 11 years old (mean age, 30 months; median age, 18 months). The plasma concentration of busulfan in all 1028 samples was measured with the same high-performance liquid chromatography method. Maximum likelihood estimates were sought for pharmacokinetic parameters with the NONMEM program. The best structural covariate-free model for busulfan was a one-compartment model with an exponential error model to account for intersubject variability and a proportional error model to account for intrasubject variability. The apparent oral clearance was found to be correlated with age, aspartate transaminase, and type of disease (malignant disease or other). The apparent volume of distribution was related to body weight. The busulfan formulation (1% powder form or crystal form) and dose (milligrams per kilogram) influenced the absorption rate constant. It was estimated that oral clearance expressed per kilogram of body weight is low at early infancy, then increases to a maximum at approximately 2 years of age and, thereafter, decreases. In conclusion, we have developed a population pharmacokinetic model of oral busulfan in children, particularly for those younger than 4 years old, that takes into consideration not only body size, but also several other covariates.

Original languageEnglish
Pages (from-to)75-83
Number of pages9
JournalTherapeutic Drug Monitoring
Volume30
Issue number1
DOIs
Publication statusPublished - Feb 1 2008
Externally publishedYes

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Keywords

  • Busulfan
  • Hematopoietic stem cell transplantation
  • Population pharmacokinetics
  • Therapeutic drug monitoring
  • Young children

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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