Russell J A, Kangarloo S B
Alberta Blood & Marrow Transplant Program, Tom Baker Cancer Centre, 1331-29 St NW, Calgary, T2N 4N2, Canada.
Curr Pharm Des. 2008;14(20):1936-49. doi: 10.2174/138161208785061382.
Busulfan is the only agent used in myeloablative regimens for hematopoietic stem cell transplantation for which therapeutic drug monitoring (TDM) has been widely used. Studies of oral busulfan (Bu) indicate wide intrapatient and interpatient variations in pharmacokinetic (PK) behavior, particularly in children. Dose adjustments of oral Bu based on TDM to bring exposures within established therapeutic ranges have been shown to reduce toxicity and improve outcomes. Intravenous (IV) Bu is becoming more widely used and has much more predictable PK. Outcomes with IV Bu appear to be superior to those achieved using oral Bu without TDM. However there is still at least a threefold variation in exposures achieved by the same dose of IV Bu in different individuals and a small proportion of patients will experience toxic exposures with current dosing regimens. Therapeutic monitoring with appropriate dose adjustment is therefore recommended for all patients treated with regimens containing high doses of Bu. Giving IV Bu at a fixed rate to adults will narrow the range of exposures but more work is needed to establish the best dosing regimen to bring as many exposures as possible within the target range. Studies of test dosing of IV Bu show that this strategy is more accurate when test and treatment doses are infused at the same rate. Finally, targeting exposures to the upper end of the therapeutic range may provide a safe approach to exploiting dose-intensity for the treatment of some malignancies.
白消安是唯一一种用于造血干细胞移植清髓方案的药物，治疗药物监测（TDM）已广泛应用于该药物。口服白消安（Bu）的研究表明，患者体内和患者之间的药代动力学（PK）行为存在很大差异，尤其是在儿童中。基于TDM调整口服Bu剂量以使暴露量处于既定治疗范围内，已被证明可降低毒性并改善治疗结果。静脉注射（IV）Bu的使用越来越广泛，其PK更具可预测性。IV Bu的治疗效果似乎优于未进行TDM的口服Bu。然而，不同个体使用相同剂量的IV Bu所达到的暴露量仍至少有三倍的差异，并且一小部分患者在当前给药方案下会出现毒性暴露。因此，建议对所有接受含高剂量Bu方案治疗的患者进行治疗监测并适当调整剂量。以固定速率给成人静脉注射Bu将缩小暴露量范围，但需要更多工作来确定最佳给药方案，以使尽可能多的暴露量处于目标范围内。IV Bu试验给药的研究表明，当试验剂量和治疗剂量以相同速率输注时，该策略更准确。最后，将暴露量目标设定在治疗范围的上限可能为利用剂量强度治疗某些恶性肿瘤提供一种安全的方法。
