Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study

Abstract

An IV form of busulfan (IV Bu) has recently become available for high dose conditioning regimen before haematopoietic stem cell transplantation (HSCT). This IV form is expected to reduce the high pharmacokinetic variability exhibited with oral busulfan and as a result, to better target the plasma area under the curve (AUC). Pharmacokinetics (PK) of IV Bu was investigated on 127 adult patients (333 PK administrations) who received 0.8 mg.kg-1 of Bu as a 2-h infusion every 6 h over 4 days, followed by cyclophosphamide (60 mg.kg-1 day-1x2). A retrospective population PK analysis was carried out to search for important predictive factors of IV Bu PK and to develop a limited sampling strategy (LSS) through Bayesian methodology. The analysis was conducted using the Non Linear Mixed Effect methodology and included a validation process on an independent data set. Adjusted Ideal Body Weight (AIBW) and Body Surface Area (BSA) were the best covariates to explain the inter-patient variability. The final inter-patient variability (CV=16%) in IV Bu clearance (Cltot) was estimated close to the intra-patient variability (CV=13%). There was neither age-dependency nor gender effect. IV Bu Cltot was not affected by elevated hepatic enzymes or by co-administration of either fluconazole or acetaminophen, and was not altered in heavily pre-treated or pre-transplanted patients. Normalised Cltot based on either AIBW or BSA was comparable between normal and obese patients (BMI=18-26.9 kg.m-2, >26.9 kg.m-2, respectively) whereas significant differences existed when based on either actual (ABW) or ideal body weight (IBW). As a consequence, no dose adjustment is required in obese patients when using a AIBW- or BSA-based dose calculation. A fixed dose of 0.80 mg.kg-1 of AIBW or 29 mg.m-2 of BSA yielded an average AUC of 1,200 microM.min, with 80% of patients within the "therapeutic" AUC range of 900-1,500 microM.min. Alternatively, 0.80 mg.kg-1 based on either ABW or IBW for normal patients and on AIBW for obese patients would achieve the same performance. A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset: AUCs obtained from one to two samplings were demonstrated to be reliably estimated.

Exposure equivalence between IV (0.8 mg/kg) and oral (1 mg/kg) busulfan in adult patients

“…The influence of dosing calculation on the plasma exposure to the drug has already been demonstrated in previous studies on oral [10] and IV Bu [5].…”

“…Since a frequently used and recommended [5,26] dosing protocol is ABW for patients of normal weight (BMI< 27 kg/m²) and AIBW for obese patients (BMI≥27 kg/m²), all AUC values were normalised according to this dosing protocol.…”

“…Busulfan is mainly eliminated by the liver [1][2][3] where it is converted into inactive metabolites by a glutathione-reductase-dependent mechanism involving glutathion-S-transferase enzymes [4,5]. Renal elimination of Bu is known to be minor; about 2% of the unchanged drug is excreted in the urine [6,7].…”

Outcomes after autologous SCT in lymphoma patients grouped by weight

“…Ultimately, therapeutic drug monitoring was not performed during this study and therefore we cannot assess the true impact of the different BU formulations. [22][23][24] Therapeutic drug monitoring and subsequent pharmacokinetic directed dosing of BU, regardless of formulation, has been associated with lower non-relapse mortality and improved OS and PFS. [25][26][27] Pharmacokinetic directed dosing of BU may optimize therapy further and limit potential toxicities.…”

Population Pharmacokinetics of Busulfan in Children: Increased Evidence for Body Surface Area and Allometric Body Weight Dosing of Busulfan in Children

“…In addition, especially when giving busulfan orally, co-medications like phenytoin, metronidazole, and azole antifungals, which are prescribed for seizure and infection prophylaxis (33), have been shown to influence busulfan clearance although they do not play a major role when busulfan is administered intravenously. Intravenous formulations of busulfan are given with more priority to reduce the high PK variability (34).…”