Tominaga T, Hayashi K, Hayasaka A, Asaishi K, Abe R, Kimishima I, Izuo M, Iino Y, Yokoe T, Abe O
Dept. of Surgery, Tokyo Metropolitan Kamagome Hospital.
Gan To Kagaku Ryoho. 1992 Dec;19(14):2363-72.
A phase I study of NK 622 (toremifene citrate), a novel antiestrogen, was conducted in female patients with cancer. Patients received a single oral dosing or daily once oral dosing for five consecutive days. Any adverse effects were not experienced in the single dosing of 40 or 60 mg of NK 622. In the daily administration of 10, 20, 40, 60, 120, 240 and 480 mg/day, one of three patients who received 20 mg/day experienced grade 1 anorexia, three of four patients received 240 mg/day experienced adverse effects: Grade 1 leukopenia in one patient, Grade 1 general hot flush in one patient, and Grade 1 nausea, hot flush in the face and vertigo, Grade 2 anorexia, fatigue, dull headache and general hot flush in another one patient. These symptoms recovered to normal levels after treatment. Serum hormone levels were examined in postmenopausal patients, and a significant increase of the sex hormone binding globulin level was observed in the patients received 120 and 240 mg/day doses. Serum levels of NK 622 determined as free base (TOR) reached the peak levels in 2 to 4 hours after administration on the 1st and 5th day in daily treatment, while a metabolite N-demethyltoremifene (TOR-1) reached the peak level in 4 to 170 hours. Maximum serum levels and area under the concentration versus time curves of TOR and TOR-1 increased dose-dependently. These values also increased by repetition of the treatment. Half-lives of TOR and TOR-1 in serum ranged in 74.5 to 148.9 hours and 154.1 to 653.1 hours, respectively. From these results, it was concluded that safety and efficacy of NK 622 should be assessed by using 240 mg or less doses in clinical phase II studies where breast cancer patients received long term treatment with NK 622.
对新型抗雌激素药物NK 622（枸橼酸托瑞米芬）进行了一项I期研究，研究对象为女性癌症患者。患者接受单次口服给药或连续5天每日一次口服给药。40或60 mg NK 622单次给药未出现任何不良反应。在每日服用10、20、40、60、120、240和480 mg/天的情况下，接受20 mg/天的3名患者中有1名出现1级厌食；接受240 mg/天的4名患者中有3名出现不良反应：1名患者出现1级白细胞减少，1名患者出现1级全身性潮热，另1名患者出现1级恶心、面部潮热和眩晕、2级厌食、疲劳、钝痛性头痛和全身性潮热。这些症状在治疗后恢复到正常水平。对绝经后患者的血清激素水平进行了检测，接受120和240 mg/天剂量的患者中观察到性激素结合球蛋白水平显著升高。在每日治疗的第1天和第5天，以游离碱（TOR）测定的NK 622血清水平在给药后2至4小时达到峰值，而代谢物N - 去甲基托瑞米芬（TOR - 1）在4至170小时达到峰值水平。TOR和TOR - 1的最大血清水平以及浓度 - 时间曲线下面积呈剂量依赖性增加。这些值也因治疗的重复而增加。TOR和TOR - 1在血清中的半衰期分别为74.5至148.9小时和154.1至653.1小时。从这些结果得出结论，在乳腺癌患者接受NK 622长期治疗的II期临床研究中，应使用240 mg或更低剂量评估NK 622的安全性和有效性。
