Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation (original) (raw)
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.
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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
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Authors and Affiliations
- The Johns Hopkins Oncology Center, 600 North Wolfe Street, 21205, Baltimore, MD, USA
Louise B. Grochow, Richard J. Jones, Robert B. Brundrett, Hayden G. Braine, Tian-Ling Chen, Rein Saral, George W. Santos & O. Michael Colvin
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- Louise B. Grochow
You can also search for this author inPubMed Google Scholar - Richard J. Jones
You can also search for this author inPubMed Google Scholar - Robert B. Brundrett
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You can also search for this author inPubMed Google Scholar - Rein Saral
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Supported in part by NCI PO1-CA15396
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Grochow, L.B., Jones, R.J., Brundrett, R.B. et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation.Cancer Chemother. Pharmacol. 25, 55–61 (1989). https://doi.org/10.1007/BF00694339
- Received: 24 October 1988
- Accepted: 04 April 1989
- Issue Date: January 1989
- DOI: https://doi.org/10.1007/BF00694339