Newman E M, Carroll M, Akman S A, Chow W, Coluzzi P, Hamasaki V, Leong L A, Margolin K A, Morgan R J, Raschko J W, Shibata S, Somlo G, Tetef M, Yen Y, Ahn C W, Doroshow J H
Division of Pediatrics, City of Hope Cancer Research Center, Duarte, CA 91010, USA.
Cancer Chemother Pharmacol. 1997;39(3):254-8. doi: 10.1007/s002800050569.
A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/ m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R2 = 0.71, n = 18, P < 0.0001). The mean +/- SE concentrations were 93 +/- 16, 230 +/- 6 and 302 +/- 27 microM at 1, 2 and 3.2 g/m2 per day, respectively. The mean +/- SE renal and nonrenal clearances of hydroxyurea were 2.14 +/- 0.18 and 3.39 +/- 0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean +/- SE half-life of 3.25 +/- 0.18 h (n = 17). The steady-state concentration of hydroxyurea was > 200 microM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.
一组18例晚期癌症患者进入了一项关于羟基脲120小时持续静脉输注的I期研究。羟基脲的剂量在患者队列中从每天1克/平方米逐步递增至2克/平方米，再到3.2克/平方米。主要的剂量限制性毒性是中性粒细胞减少，常伴有白细胞减少、血小板减少和全身性皮疹。用地塞米松和盐酸苯海拉明对患者进行预防性治疗可预防皮疹，但不能预防血液学毒性。对所有患者都进行了羟基脲的药代动力学研究。羟基脲的稳态浓度与剂量呈线性相关（R2 = 0.71，n = 18，P < 0.0001）。每天1、2和3.2克/平方米时，平均±标准误浓度分别为93±16、230±6和302±27微摩尔。羟基脲的平均±标准误肾脏清除率和非肾脏清除率分别为每平方米2.14±0.18和3.39±0.28升/小时（n = 16），两者均与剂量无关。血浆中羟基脲的浓度呈单指数衰减，平均±标准误半衰期为3.25±0.18小时（n = 17）。在每天2克/平方米治疗的所有9例患者中，羟基脲的稳态浓度均>200微摩尔，该剂量在5天内耐受性良好。我们推荐该剂量用于与其他抗肿瘤药物联合进行的II期试验。
