Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders

M. Hassan*, A. Fasth, B. Gerritsen, A. Haraldsson, Z. Syrůčková, H. Van Den Berg, M. Sandström, M. Karlsson, S. Kumlien, J. Vossen

*Corresponding author for this work

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75 Citations (Scopus)

Abstract

Busulphan pharmacokinetics were investigated in 20 children, who underwent bone marrow transplantation for either leukemia or inherited disorders. Busulphan (1.90-6.02 mg/kg/day) was administered orally as a single dose or twice daily. Busulphan kinetics were found to be linear within the studied range. Children with inherited disorders eliminated busulphan significantly faster after the first and the last dose with half-lives (t( 1/4 )) of 1.93 and 1.71 h, respectively compared to children with leukemia (3.16 and 2.70 h, respectively). The area under plasma concentration curves (AUCs, corrected for mg/kg) as an expression for the systemic exposure of busulphan were significantly higher in children with leukemia, 22.4 and 19.04 μmol/l.h (5527 and 4690 ng.h.ml-1) after the first and the last dose, respectively, compared to 11.2 and 8.2 μmol/l.h (2768 and 2029 ng.h.ml-1) found in children with inherited disorders. The present results confirm those reported by others, ie busulphan pharmacokinetics can be influenced by the underlying disease and its status. Our population pharmacokinetic analysis showed a negative correlation between the weight corrected clearance and the age in both groups of children. However, clearance was about 42% higher in children with inherited disorders compared to those with leukemia. To estimate AUC for the first dose, we evaluated a limited sampling model based on three concentrations (1, 3 and 6 h). A high correlation (r = 0.998, P < 0.0001, n = 40) between the estimated and the determined AUC was found. The present model is reliable and adequate for studying more patients, with a long-term follow-up combined with drug monitoring in correlation with drug efficacy and toxicity to define the optimal busulphan dosage required.

Original languageEnglish
Pages (from-to)843-850
Number of pages8
JournalBone Marrow Transplantation
Volume18
Issue number5
Publication statusPublished - Nov 1996

Other keywords

  • Bone marrow transplantation
  • Busulphan
  • Inherited disorders
  • Leukemia
  • Pediatric
  • Pharmacokinetics

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