Cancer Chemotherapy and Pharmacology

, Volume 25, Issue 1, pp 55–61

Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation

  • Louise B. Grochow
  • Richard J. Jones
  • Robert B. Brundrett
  • Hayden G. Braine
  • Tian-Ling Chen
  • Rein Saral
  • George W. Santos
  • O. Michael Colvin
Original Articles Busulfan Kinetics, Bone Marrow Transplantation, Pharmacokinetics

DOI: 10.1007/BF00694339

Cite this article as:
Grochow, L.B., Jones, R.J., Brundrett, R.B. et al. Cancer Chemother. Pharmacol. (1989) 25: 55. doi:10.1007/BF00694339

Summary

Busulfan is an alkylating agent that is widely used in preparative regimens for bone marrow transplantation (BMT). We developed a high-performance liquid chromatographic (HPLC) assay for the determination of plasma busulfan concentrations in 30 patients who received oral doses of 1 mg/kg. Concentrations were fit by a one-compartment pharmacokinetic model with first-order absorption. The pattern of absorption and elimination varied widely between patients, with peak concentrations ranging from 1.2 to 10.4 μmol/l (mean, 4.25±2.49). The climination half-life ranged from 58 to 433 min (harmonic mean, 140 min). The AUC contributed by a single oral dose ranged from 606 to 5,144 μmol-min/l (mean, 2,012±1,223). Patients were evaluated for the development of veno-occlusive disease (VOD), a treatment complication that occurs in 20% of patients undergoing BMT and causes 10% of transplantation-related deaths. All six patients who developed VOD had an AUC greater than the mean, and five of them had an AUC that was >1 SD above the mean. The occurrence of VOD was highly correlated with an increased AUC (>1 SD above the mean) (X2=18;P<0.0001). Using multivariate logistic regression, no other statistically significant pharmacokinetic predictor of VOD was found. The tenfold variability in the busulfan AUC and the statistical association of increased AUC with the development of VOD suggest a possible role for therapeutic monitoring in this setting.

Abbreviations

VOD

veno-occlusive disease of the liver

BMT

bone marrow transplantation

ka

absorption rate constant

k

elimination rate constant

tlag

absorption lag time

V

volume of distribution

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Louise B. Grochow
    • 1
  • Richard J. Jones
    • 1
  • Robert B. Brundrett
    • 1
  • Hayden G. Braine
    • 1
  • Tian-Ling Chen
    • 1
  • Rein Saral
    • 1
  • George W. Santos
    • 1
  • O. Michael Colvin
    • 1
  1. 1.The Johns Hopkins Oncology CenterBaltimoreUSA