Tricot G, Alberts D S, Johnson C, Roe D J, Dorr R T, Bracy D, Vesole D H, Jagannath S, Meyers R, Barlogie B
Division of Hematology/Oncology and Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Clin Cancer Res. 1996 Jun;2(6):947-52.
Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.
美法仑（MEL）可能是多发性骨髓瘤（MM）中最有效的化疗药物，具有明确的剂量反应效应。它可以在不过度毒性的情况下增加到200mg/m²，这是一个需要造血干细胞支持的清髓剂量。肾功能明显不全的患者在MM中并不少见，他们要么接受了减量治疗，要么被排除在高剂量MEL治疗之外。进行了一项前瞻性研究，以评估20例MM患者中MEL药代动力学与肾功能之间的关系。6例患者有严重肾功能不全（肌酐清除率<40ml/min），其中5例接受慢性血液透析。3例严重肾功能损害患者首先接受低剂量MEL测试剂量（16mg/m²）用于药代动力学研究。所有患者接受200mg/m²的MEL，分为两个100mg/m²的等份静脉注射，连续2天给药，随后输注外周血干细胞。在首次给予100mg/m²剂量后进行的MEL药代动力学研究未受肾功能损害的不利影响。肌酐清除率<40ml/min的患者中，MEL的中位半衰期（t1/2）、浓度曲线下面积和清除率分别为1.1小时、5.5mg·h/升和27.5升/小时，而其他患者分别为1.9小时、7.9mg·h/升和23.6升/小时。肾功能不全对外周血干细胞采集质量也没有明显负面影响，对移植后植入、输血需求、严重粘膜炎发生率或总生存期也没有不利影响。然而，它与发热持续时间延长（P=0.0005）和住院时间延长（P=0.004）有关。未观察到与移植相关死亡。血浆t1/2和浓度曲线下面积在最低值和最高值患者之间相差10倍，MEL清除率相差5倍。MEL消除的这些巨大差异无法用患者或疾病特征来解释。我们得出结论，在自体移植中，肾功能衰竭不需要降低MEL剂量。由于MEL消除存在明显的个体间差异，药代动力学指导给药以及细胞药理学研究可能有助于实现更均匀的抗肿瘤效果。
