Busulfan dose Recommendation in Inherited Metabolic Disorders: Population Pharmacokinetic Analysis

Takuto Takahashi, Sílvia M. Illamola, Cathryn A. Jennissen, Susan E. Long, Troy C Lund, Paul J. Orchard, Ashish O Gupta, Janel R. Long-Boyle

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Busulfan is a commonly used alkylating agent in the conditioning regimens of hematopoietic cell transplantation (HCT). Population pharmacokinetic (popPK) models enable description of busulfan PK and optimization of exposure, which leads to improvement of event-free survival after HCT. Prior busulfan popPK analysis has been limited by small numbers in patients with inherited metabolic disorders (IMD). The primary objective was to characterize population PK of busulfan in a large cohort of children and young adults undergoing HCT for IMD. PopPK analysis of busulfan drug concentrations was performed using data from 78 patients with IMD who received intravenous busulfan (every 24 hours, 4 doses) as part of pretransplantation combination chemotherapy. The final model for busulfan drug clearance was used to estimate individual doses aimed to achieve a target cumulative area under the curve (cAUC) of 80 to 100 mg · h/L. We then compared the probability of cAUC within the range of 80 to 100 mg · h/L by the developed dosing regimen versus conventional regimen. A 1-compartment, linear elimination model best described the PK of busulfan. Significant covariates demonstrated to affect busulfan clearance included total body weight and the time (in days) from busulfan infusion start. The probability of target cAUC attainment by the developed dosing versus the conventional dosing were 47% versus 43% for body weight <12 kg, and 48% versus 36% for body weight ≥12 kg. We described population PK of intravenous busulfan in a large IMD cohort. The proposed dosing regimen based on the developed model can improve the target cAUC attainment of busulfan for IMD.

Original languageEnglish (US)
Pages (from-to)104.e1-104.e7
JournalTransplantation and Cellular Therapy
Volume28
Issue number2
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
Financial disclosure: Nothing to declare. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: TT, AOG, and JRLB conceptualized the study. CAJ and SEL provided data. All analyses was conducted by TT, supported by SMI, and supervised by JRLB. TT wrote the original draft, and all authors contributed to reviewing and editing.

Publisher Copyright:
© 2021 The American Society for Transplantation and Cellular Therapy

Keywords

  • Busulfan
  • Hematopoietic cell transplantation
  • Inherited metabolic disorders
  • NONMEM
  • Population pharmacokinetics

PubMed: MeSH publication types

  • Journal Article

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