Aspects concerning busulfan pharmacokinetics and bioavailability

Busulfan as a high-dose therapy is an important component of many of the myeloablative regimens for both allogeneic and autologous bone marrow transplantation (BMT) in adults and children. During the last decade, several studies have shown a wide inter- and intra-patient variability of busulfan disposition in adults and children. Some of the factors affecting the interpatient-variability were identified as circadian rhythmicity, age, disease, drug interaction, alteration in hepatic function and recently busulfan bioavailability. In adults, pharmacodynamic studies have shown a positive correlation between high-systemic exposure of the drug and venocclusive disease (VOD). However, pharmacodynamic studies in children did not establish any correlation between the systemic exposure and VOD. Drug-monitoring and dose adjustment in adults were used successfully to decrease the occurrence of VOD and mortality. It was observed that about 20% of the busulfan dose crosses the blood brain barrier, The high amount of the drug which enters the brain can probably be involved in the CNS toxicities reported. In children, a low rate of toxicity combined with a high rate of engraftment failure were observed, Several investigators have expressed their concern about the dosage in children and many suggested higher doses based on the body surface area for young children. However, recently it was shown that busulfan bioavailability varied by 2-fold in adults (0.5-1.03) while in children a B-fold variation:vas observed (0.22-1.20). The access to an intravenous form of busulfan and a deeper understanding of pharmacodynamics of the drug might be essential to optimize the treatment, reach a successful engraftment and lower the therapy related toxicities.