A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia.
A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia.
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DOI：
10.1038/sj.bjc.6603265
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发表时间：
2006-08-07
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
为了确定半合成高三尖杉酯碱 (ssHHT) 的最大耐受剂量 (MTD)、剂量限制毒性和药代动力学，每天两次皮下 (s.c.) 注射，持续 9 天，在晚期急性白血病患者中，18 名晚期急性髓性白血病患者被纳入这项序贯贝叶斯 I 期剂量探索试验。探索了 0.5mg m−2 day−1 的起始剂量，随后剂量递增为 1、3、5 和 6mg m−2 day−1。骨髓抑制是持续的。 MTD 估计为皮下注射连续 9 天 5 mg m−2 day−1 的剂量水平。路线。剂量限制性毒性为 3 mg m−2 时出现高血糖伴高渗性昏迷，以及 (i) 一种恶心和吐血，(ii) 一种危及生命的肺曲霉菌病，(iii) 一种皮疹和 (iv) 一种剂量水平为 5 mg m−2 day−1 时的头皮疼痛。 ssHHT的平均半衰期为11.01±3.4 h，稳态分布容积为2±1.4 l kg−1，血浆清除率为11.6±10.4 l h−1。 12 名循环白血病细胞患者中，有 11 名患者获得了血液母细胞清除，两名患者获得完全缓解，一名患有 CMML 母细胞危象的患者返回慢性期。 9 天方案中 ssHHT 的推荐每日剂量为 5 mg m−2 day−1。
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m−2 day−1 was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m−2 day−1. Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m−2 day−1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m−2, and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m−2 day−1. The mean half-life of ssHHT was 11.01±3.4 h, the volume of distribution at steady state was 2±1.4 l kg−1 and the plasma clearance was 11.6±10.4 l h−1. Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m−2 day−1.
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DOI：
10.1111/j.1432-1033.1977.tb11256.x
发表时间：
1977-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
FRESNO, M;JIMENEZ, A;VAZQUEZ, D
通讯作者：
VAZQUEZ, D
影响因子：
1.9
作者：
OQUIGLEY, J;PEPE, M;FISHER, L
通讯作者：
FISHER, L
影响因子：
2.1
作者：
Büchner, T;Hiddemann, W;Heinecke, A
通讯作者：
Heinecke, A
影响因子：
6.2
作者：
Marin, D;Kaeda, JS;Apperley, JF
通讯作者：
Apperley, JF
影响因子：
6.2
作者：
O'Brien, S;Giles, F;Kantarjian, HM
通讯作者：
Kantarjian, HM