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Pharmacokinetics

Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens

Bone Marrow Transplantation volume 28, pages 743–751 (2001)Cite this article

Abstract

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 μg.h.ml+1. Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan–Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 ± 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients. Bone Marrow Transplantation (2001) 28, 743–751.

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Acknowledgements

This work was supported by a grant from Hospices Civils de Lyon, 3 Quai des Célestins, 69002 Lyon, and by the association ‘LE DEFI ANTHONY’, Mont Talon, 71800 St Symphorien des Bois, France.

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Authors and Affiliations

  1. Department of Pharmacy, Debrousse Hospital, Lyon, France

    N Bleyzac, P Magron, A Janoly, P Martin & G Aulagner

  2. Department of Paediatric Immuno-haematology and Bone Marrow Transplantation, Debrousse Hospital, Lyon, France

    G Souillet, Y Bertrand, C Galambrun & Q Dai

  3. ADCAPT, A Charial Hospital, Francheville, France

    N Bleyzac, P Martin & P Maire

  4. Laboratory of Applied Pharmacokinetics, University of Southern California, School of Medicine, Los Angeles, CA, USA

    P Maire & RW Jelliffe

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Bleyzac, N., Souillet, G., Magron, P. et al. Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens. Bone Marrow Transplant 28, 743–751 (2001). https://doi.org/10.1038/sj.bmt.1703207

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