PHASE-I CLINICAL AND PHARMACOKINETIC TRIAL OF DEXTRAN CONJUGATED DOXORUBICIN (AD-70, DOX-OXD)
PHASE-I CLINICAL AND PHARMACOKINETIC TRIAL OF DEXTRAN CONJUGATED DOXORUBICIN (AD-70, DOX-OXD)
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DOI：
10.1007/bf00874153
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发表时间：
1993-01-01
影响因子：
3.4
通讯作者：
HANAUSKE, AR
中科院分区：
文献类型：
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作者：
DANHAUSERRIEDL, S;HAUSMANN, E;HANAUSKE, AR
蒽环类药物与高分子量载体偶联可能改变药物分布并提高抗肿瘤效果。我们进行了一项多柔比星与葡聚糖（分子量70000）偶联物的I期临床试验。该药物每21 - 28天静脉单次给药。13名患者共接受了24个疗程（中位数为2；范围1 - 3）。在多柔比星等效剂量（DOXeq）为40mg/m²的起始剂量下，2名患者中有2名出现世界卫生组织（WHO）Ⅳ级血小板减少症。一名原有心脏病的患者出现WHO Ⅳ级肝毒性和WHO Ⅲ级心脏毒性。5名患者接受了12.5mg/m² DOXeq的治疗。在此剂量水平下，最大毒性反应为1/5名患者出现WHO Ⅲ级血小板减少症和局部静脉炎（WHO Ⅱ级），另一名患者出现碱性磷酸酶升高（WHO Ⅲ级）和WHO Ⅲ级呕吐。随后，5名患者接受了20mg/m² DOXeq。5/5名患者出现肝毒性（1例为WHO Ⅳ级，1例为WHO Ⅲ级）。3/5名患者出现血小板减少症（1例为WHO Ⅳ级，2例为WHO Ⅲ级）。在12.5mg/m² DOXeq剂量下，一名被诊断为恶性纤维组织细胞瘤的患者病情稳定了4个月。对血浆和尿液中的总多柔比星和游离多柔比星进行了药代动力学分析。在40mg/m² DOXeq时，总多柔比星的最大血浆峰浓度（ppc）为12.3μg/ml。血浆浓度 - 时间曲线下面积（AUC）范围为28.83 - 80.21μg/ml·h，消除半衰期呈剂量依赖性（t₁/₂α：0.02 - 0.87h；t₁/₂β：2.69 - 11.58h；t₁/₂γ：41.44 - 136.58h）。我们得出结论，使用该方案时AD - 70的最大耐受剂量（MTD）为40mg/m² DOXeq。Ⅱ期临床研究的推荐剂量为12.5mg/m² DOXeq。
Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21-28 days. Thirteen patients have received a total of 24 courses (median 2; range 1 - 3). At the starting dose of 40 Mg/M2 doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 115 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 Mg/M2 DOXeq. Hepatotoxicity was noted in 515 patients (I x WHO grade IV, 1 x WHO grade III). Thrombocytopenia was noted in 3/5 patients (I x WHO grade IV, 2 x WHO grade III). At 12.5 Mg/M2 DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 mug/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83-80.21 mug/ml*h with dose-dependent elimination half lives (t1/2alpha: 0.02-0.87 h; t1/2beta: 2.69-11.58 h; t1/2gamma: 41.44-136.58 h). We conclude that the maximal tolerated dose (MTD) of AD-70 using this schedule is 40 mg/m2 DOXeq. The recommended dose for clinical phase II studies is 12.5 Mg/M2 DOXeq.