Andersson B S, Madden T, Tran H T, Hu W W, Blume K G, Chow D S, Champlin R E, Vaughan W P
Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston 77005, USA.
Biol Blood Marrow Transplant. 2000;6(5A):548-54. doi: 10.1016/s1083-8791(00)70064-4.
The unpredictable intestinal absorption and erratic bioavailability of oral busulfan (Bu) has limited the drug's use in high-dose pretransplantation conditioning therapy. To standardize drug delivery, we solubilized Bu for parenteral use. This new intravenous (i.v.) Bu formulation was combined with oral Bu and cyclophosphamide (Cy) to evaluate (1) the human acute toxicity of i.v. Bu and its solvent system and (2) the pharmacokinetics of Bu in patients undergoing hematopoietic progenitor cell transplantation (HPCT). One dose of i.v. Bu (escalating from 0.08 to 0.8 mg/kg) was given over 2 hours by pump; 6 hours later, an oral Bu regimen was begun, consisting of 1 mg/kg every 6 hours for 15 doses, followed by Cy, 60 mg/kg daily for 2 days. After 1 day of rest, HPCT was performed. The i.v. Bu dose was well tolerated and did not produce any acute toxicity reaction that could be attributed to the solvent system of dimethylacetamide and polyethylene glycol (PEG)-400. All observed treatment-related toxicity was as would be expected after high-dose oral Bu plus Cy. When the i.v. Bu was used as reference solution, the pharmacokinetic analysis indicated an average bioavailability of oral high-dose Bu of 69%, ranging from <10% to virtually 100%. Further, the 2-hour infusion of i.v. Bu gave a time to maximum plasma concentration following drug administration similar to that of oral Bu (2 hours and 1.8 hours, respectively), and i.v. Bu had a clearance similar to that of oral Bu. Based on the data in this study, we suggest that the optimal (starting) dose of i.v. Bu (in combination with Cy) in our forthcoming phase 2 trial should be on the order of 0.8 mg/kg to target an area under the curve (AUC) of 1100 to 1200 micromol/L per minute. This would secure myeloablation and engraftment but save the vast majority of patients from the increased risk of serious hepatic veno-occlusive disease that has been reported when the AUC level exceeds 1500 micromol/L per minute. Bu administration via the i.v. route will assure complete bioavailability and reliable systemic drug exposure with more predictable blood levels and, therefore, possibly lower the risks for serious/life-threatening toxicity, graft rejection, and recurrent leukemia.
口服白消安（Bu）难以预测的肠道吸收和不稳定的生物利用度限制了该药物在高剂量移植前预处理治疗中的应用。为了规范给药，我们将白消安制成了可供肠胃外使用的溶液。这种新的静脉注射（i.v.）白消安制剂与口服白消安及环磷酰胺（Cy）联合使用，以评估（1）静脉注射白消安及其溶剂系统对人体的急性毒性，以及（2）白消安在接受造血祖细胞移植（HPCT）患者中的药代动力学。通过泵在2小时内给予一剂静脉注射白消安（剂量从0.08毫克/千克递增至0.8毫克/千克）；6小时后，开始口服白消安方案，即每6小时服用1毫克/千克，共15剂，随后给予环磷酰胺，每天60毫克/千克，持续2天。休息1天后，进行造血祖细胞移植。静脉注射白消安的剂量耐受性良好，未产生任何可归因于二甲基乙酰胺和聚乙二醇（PEG）-400溶剂系统的急性毒性反应。所有观察到的与治疗相关的毒性反应与高剂量口服白消安加环磷酰胺后的预期情况一致。以静脉注射白消安作为参比溶液时，药代动力学分析表明口服高剂量白消安的平均生物利用度为69%，范围从<10%至几乎100%。此外，静脉注射白消安2小时输注后的给药后达血浆最大浓度时间与口服白消安相似（分别为2小时和1.8小时），且静脉注射白消安的清除率与口服白消安相似。基于本研究中的数据，我们建议在即将开展的2期试验中，静脉注射白消安（与环磷酰胺联合使用）的最佳（起始）剂量应为0.8毫克/千克左右，以达到曲线下面积（AUC）为每分钟1100至1200微摩尔/升的目标。这将确保骨髓消融和植入，但能使绝大多数患者避免当AUC水平超过每分钟1500微摩尔/升时所报道的严重肝静脉闭塞病风险增加的情况。通过静脉途径给药白消安将确保完全生物利用度和可靠的全身药物暴露，血药水平更可预测，因此可能降低严重/危及生命毒性、移植物排斥和复发性白血病的风险。
