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

Abstract

Summary: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 g.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

In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa)

“…17 Pharmacokinetically guided dose adjustment for BU CY is being performed and explored by several teams. [18][19][20][21] In contrast, we have previously reported the absence of such a pharmacodynamic relationship when busulfan is combined with other alkylating agents. 22 In that previous study, several high-dose busulfan-containing regimens were evaluated and 39 out of 61 patients received three alkylating agents, namely busulfan, cyclophosphamide combined with either melphalan or thiotepa.…”

“…However, data are lacking to demonstrate a relationship between overexposure to busulfan and liver toxicity in children and to define a maximum threshold in this population. 17,34 The therapeutic window (3600-5400 h ng ml À1 ) developed for adults has however been successfully applied in children 19,21 under treatment with BU CY in whom therapeutic drug monitoring (TDM) was mainly aimed at ensuring engraftment with exposure to busulfan exceeding 3600 h ng ml À1 . The therapeutic window defined for BU CY cannot be used prospectively to adjust the dose of busulfan in children treated with BU MEL or BU TTP regimens.…”

I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients

“…[8][9][10]14,18,27 Therapeutic drug monitoring is intended to reduce the high variation in plasma exposure following oral administration. However, this strategy is not accessible to all investigator centers and is seldom implemented in clinical settings because blood collection and samples handling call for specific laboratory equipment, prompt analysis using a reliable and rapid assay method for plasma drug determination as well as skilled nursing staff.…”

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

“…[1][2][3][4] Intravenous (IV) administration has consequently gained popularity, especially in children, as IV pharmacokinetics can be more predictive than pharmacokinetics after oral administration. [5][6][7] Nevertheless, important interindividual variability still persists 8 and several additional factors contribute to such observations. Metabolism by glutathione S-transferase (GST) is the main route of BU biotransformation.…”