A Simple Approximation for Busulfan Dose Adjustment in Adult Patients Undergoing Bone Marrow Transplantation

Abstract

Busulfan is an alkylating agent used in preparative regimens before bone marrow transplantation (BMT). Busulfan concentrations in plasma, expressed as the area under the concentration-time curve (AUC), were reported to correlate with treatment outcome. Because busulfan is administered in 16 doses of 1 mg/kg every 6 hours for 4 days, the opportunities to "correct" the dose as a consequence of the measured AUC are limited to the 16-dosage protocol. In the present research busulfan pharmacokinetics were prospectively evaluated in 27 adult patients treated according to the above protocol by measuring the first, second, and fifth dose AUC. The pharmacokinetic analysis was based on a noncompartment model for extravascular absorption, but calculations according to a 1-compartment model gave similar results. A simple mathematical approximation allowed prediction of the AUC of the second dose from that of the first and the busulfan concentration at trough. Fifteen patients had the dose adjusted at the fourth dose to obtain an AUC within the "therapeutic window" of 950-1500 microM-min. This procedure was then validated by the measurement of the fifth dose AUC. It appears that this simple pocket calculator method allows a rapid evaluation of the need and the extent of dose adjustment and proved to be a valuable tool to improve busulfan administration in pre BMT treatment.

Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation

“…Open and closed circles represent the value in adults and children, respectively. 20,23,26 To compare our data with the oral busulfan studies in adult patients, we used previously published data. 23 The selected study has similar sampling points to our study and individual AUC were reported.…”

“…20,23,26 To compare our data with the oral busulfan studies in adult patients, we used previously published data. 23 The selected study has similar sampling points to our study and individual AUC were reported. Several reports indicate that an AUC of 900-1500 mmol min/l 4,6,24,25 in patients receiving a conventional busulfan regimen prevents treatment failure and the risk of fatal toxicities.…”

Busulfan Use in Hematopoietic Stem Cell Transplantation: Pharmacology, Dose Adjustment, Safety and Efficacy in Adults and Children

“…Busulfan, in combination with cyclophosphamide or fludarabine, is commonly used in preparatory regimens before allogenic or autologous hematopoietic stem cell transplantation (HSCT) [3][4][5][6][7]. The primary molecular reaction for biologic activity is the alkylation of intra-cellular nucleophiles.…”

“…The usual oral dose was established to be 1 mg/kg and 1.2 mg/kg for a total of 16 doses in adult and pediatric patients, respectively [5,7,9,28,50]. Several authors have demonstrated that oral [5,6] and intravenous [32] busulfan has relatively linear pharmacokinetics allowing dose adjustment and conditioning treatment optimization using a simple pocket calculator [7,32]. According to basic principles linear pharmacokinetics implies that drug concentration increases in direct relation with the given dose.…”

Determinação de bussulfano em plasma através de cromatografia líquida de alta eficiência com detector de arranjo de diodos e derivatização com dietilditiocarbamato de sódio

“…1 Também, devido as suas propriedades mielossupressivas, é um dos medicamentos mais frequentemente utilizados em regime de altas doses em combinação com outros agentes, como a ciclofosfamida, no tratamento mieloablativo do pré-transplante de medula óssea. [1][2][3][4] Como a maioria dos agentes alquilantes, o BU apresenta uma janela terapêutica estreita e pode ter sua biodisponibilidade influenciada por fatores como idade, obesidade, ritmo circadiano e variabilidade farmacocinética intraindividual. 5 Concentrações abaixo da faixa terapêutica recomendada (concentrações em estado estacionário entre 800 a 900 ng mL -1 ) estão associadas à recorrência da doença ou à rejeição do transplante, indicando ablação incompleta da medula.…”