Phase I and pharmacokinetic study of LY309887: a specific inhibitor of purine biosynthesis
Phase I and pharmacokinetic study of LY309887: a specific inhibitor of purine biosynthesis
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DOI：
10.1007/s002800000272
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发表时间：
2001-06-01
影响因子：
3
通讯作者：
Walling, J
中科院分区：
文献类型：
--
作者：
Budman, DR;Johnson, R;Walling, J
目的：在这项人体I期试验中，评估了LY309887每周联合每日口服5毫克叶酸的安全性和药理学。背景：LY309887是参与从头嘌呤生物合成的叶酸依赖酶的抑制剂，具有广泛的临床前抗肿瘤活性。在小鼠系统中，将该药物与外源性叶酸联合使用可增强治疗指数。方法：本研究是一项单机构、开放标签、剂量递增的临床试验，并确定了毒性和药代动力学参数。研究的剂量范围为每周0.5- 4mg /m(2) x6，然后每6周修改一次计划每周x3。结果：剂量限制性毒性延迟发作，并与血液、神经和粘膜作用相关。药动学参数显示AUC和C-max呈剂量线性关系。低循环药物水平持续超过200小时。尿排泄约占母体药物的50%，但变化很大。给药后24小时内尿量接近最大值。结论：修改后的给药方案允许患者重复给药。进一步评估每周2 mg/m(2) x3每6周每日口服叶酸补充剂作为潜在的II期剂量可能是有必要的。
Purpose: In this phase I trial in humans the safety and pharmacology of LY309887 on a weekly schedule combined with daily oral 5-mg doses of folic acid were evaluated. Background: LY309887 is an inhibitor of folate-dependent enzymes involved in de novo purine biosynthesis and has a broad preclinical antitumor activity. In murine systems, combining this agent with exogenous folic acid results in an enhanced therapeutic index, Methods: This study was a single-institution, open-label, clinical trial of dose escalation with toxicity and pharmacokinetic parameters determined. The dose range studied was 0.5-4 mg/m(2) per week x6 and then a modified schedule weekly x3 every 6 weeks. Results: Dose-limiting toxicities were of delayed onset and associated with hematologic, neurologic, and mucosal effects. Pharmacokinetic parameters revealed dose linearity for AUC and C-max. Low circulating levels of drug persisted for over 200 h. Urinary excretion accounted for approximately 50% of the parent drug but was highly variable. The urinary excretion was near maximal within 24 h of dosing. Conclusions: The modified dosing schedule allowed repetitive dosing in patients. Further evaluation of the 2 mg/m(2) per week x3 every 6 weeks with daily oral folate supplement as a potential phase II dose may be warranted.