Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement

Abstract

order, were area under the curve (AUC) in mM £ min, AUC in mg £ h/L, concentration at steady state (Css) in ng/ mL, AUC in mM £ h, and AUC in mg £ h/L. All respondents conceptually agreed on the ideal properties of a BPEU and to adopt a harmonized BPEU. Respondents were equally divided between selecting AUC in mM £ min versus mg £ h/L for harmonization. AUC in mg £ h/L was finally selected as the harmonized BPEU, because it satisfied most of the survey-determined ideal properties for the harmonized BPEU and is read easily understood in the clinical practice environment. Furthermore, 10 major professional societies have endorsed AUC in mg £ h/L as the harmonized unit for reporting to HCT registry databases and for use in future protocols and publications.

Modelling of neutrophil dynamics in children receiving busulfan or treosulfan for haematopoietic stem cell transplant conditioning

“…The results of the population pharmacokinetic model developed in the current investigation (Supplementary Material 1) were consistent with those previously reported: The value of 2.84h for the terminal half-life obtained in our case resulted remarkably similar to 2.77 h as reported elsewhere [6]. In addition, the values for CL (12.2 L/h/70Kg) and Vss (47.82L/70Kg) were in accordance with those reported by McCune et al [6] (11.4 L/h/70Kg and 43.8 L/70Kg, respectively).…”

“…individualisation based on therapeutic drug monitoring (TDM) is feasible [9][10][11][12]. This fact is also applied to busulfan, for which TDM is currently done in the clinical setting [6]. In addition, the overall benefit risk and cost inform busulfan and treosulfan TDM feasibility.…”

“…Despite the fact that the PK characteristics of busulfan and treosulfan have been widely studied [6,9,[13][14][15], there are not, to our knowledge, any publications comparing innate immune reconstitution in the early post HSCT period. Sepsis and conditioning toxicity are major causes of early HSCT mortality and morbidity [16], and the dynamics of short-term innate immune reconstitution has recently been shown to predict long-term CD4+ T cell recovery [17].…”

“…Considerable inter-patient variability exists in the effectiveness and toxicity of busulfan-containing conditioning regimens. Rejection, relapse and toxicity in HSCT are associated with busulfan plasma exposure measured as area under the plasma concentration time curve (AUC) or average steady state concentration (Css), although recent guideline harmonisation suggests AUC in mg h/L should be used [6]. Therefore, personalizing busulfan doses to a target AUC is thought to improve the clinical outcomes [6,7].…”

“…Rejection, relapse and toxicity in HSCT are associated with busulfan plasma exposure measured as area under the plasma concentration time curve (AUC) or average steady state concentration (Css), although recent guideline harmonisation suggests AUC in mg h/L should be used [6]. Therefore, personalizing busulfan doses to a target AUC is thought to improve the clinical outcomes [6,7]. Treosulfan is considered to have a wider therapeutic index which has made it an attractive candidate for the use in conditioning regimens as an alternative to busulfan [8], but recent evidence suggests treosulfan dose individualisation may also be required [9,10].…”