Department of Clinical Pharmacology & Therapeutics, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Korea.
Korean J Physiol Pharmacol. 2012 Aug;16(4):273-80. doi: 10.4196/kjpp.2012.16.4.273. Epub 2012 Aug 10.
Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (V(d)) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and V(d) were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC(0-inf) (defined as median AUC(0-inf) with a once-daily dosage) of 26.18 mg/l·hr, was proposed: 24.79·ABW(0.5) mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW.
白消安是一种治疗窗较窄的抗肿瘤药物。本研究旨在分析接受造血干细胞移植的患者静脉用白消安（iBu）的群体药代动力学（PK），并对一项比较每日 1 次和每日 4 次静脉用白消安的前瞻性随机试验的事后群体 PK 分析进行了搜索，以寻找 iBu PK 的预测因素。在这项研究中，对 iBu 的群体 PK 进行了特征分析，以提供合适的给药建议。患者被随机分配接受 iBu，0.8mg/kg，每 6 小时 1 次，或 3.2mg/kg，每日 1 次，共 4 天，然后进行造血干细胞移植。共分析了 295 个白消安浓度，采用 NONMEM 法。实际体重和性别是影响 iBu PK 的重要协变量。共有 60 例患者纳入本研究（均为韩国人；女性 23 例，男性 37 例；平均年龄为 36.5[10.9]岁；体重为 66.5[11.3]kg）。对于体重 65kg 的典型患者，群体估算值为：男性 CL 为 7.6l/h，V(d)为 32.2l；女性 CL 为 29.1L。CL 和 V(d)的个体间变异性分别为 16%和 9%。基于最终 PK 模型的 CL 估算值，提出了一种简单的剂量方案，以达到目标 AUC(0-inf)（定义为每日 1 次剂量的 AUC(0-inf)中位数）26.18mg/l·hr：24.79·ABW(0.5)mg q24h，其中 ABW 代表实际体重（kg）。该剂量方案降低了 iBu CL 和 Vd 的未解释个体间变异性，ABW 是影响 iBU 清除率的重要协变量。我们提出了一种仅基于 ABW 的新的简单 iBu 给药方案。
