Nomura Y, Abe O, Enomoto K, Fujiwara K, Tominaga T, Hayashi K, Uchino J, Takahashi M, Hayasaka A, Asaishi K, Okazaki M, Abe R, Kimishima I, Kajiwara T, Haga S, Shimizu T, Miyazaki I, Noguchi M, Yoshida M, Miura S, Taguchi T, Oota J, Sakai K, Kinoshita H, Tashiro H
Dept. of Breast Surgery, National Kyushu Cancer Center.
Gan To Kagaku Ryoho. 1998 Mar;25(4):553-61.
Phase I study of TAT-59 (Miproxifen), an antiestrogen developed in Japan for breast cancer, was conducted with the collaboration of 12 hospitals. A single dose of 1.25, 5, 10, 20, 40 and 80 mg, or 5 consecutive daily doses of 1.25, 5, 10, 20 and 40 mg/day, were given orally. After single dosing, no clinical adverse effects were found. Decrease of serum Na, Cl, Ca level and increase of serum LDH level were observed in one patient after a single dose of 5 mg of TAT. An increase in the serum LDH level was also observed in one patient after a single dose in the of 10 mg of TAT. An increase in the serum LDH level and total bilirubin, increase of eosinophil, K and milky serum were also observed in one patient after a single dose of 40 mg of TAT, respectively. All of these abnormal values returned to the normal level within 26 days after final administration of TAT. No adverse clinical findings nor abnormal laboratory findings were observed after consecutive administration of TAT. After postprandial single dosing, the time to reach the maximum serum concentration (Tmax) of DP-TAT, dephosphorylated metabolite of TAT, and its demethylated metabolite, DMDP, ranged from 5.0 to 7.3 hr and from 17.0 to 42.8 hr, respectively. The maximum serum concentration (Cmax) and AUC of DP and DMDP elevated in a dose-dependent manner. T1/2 of DP and DMDP ranged from 24.2 to 41.5, and from 91.9 to 214.7 hr, respectively. There were no significant differences between pharmacokinetics of TAT before and after food intake. Based on the above results, we concluded that a Phase II study should be conducted to evaluate the efficacy, safety and optimal dose of TAT.
在12家医院的合作下，开展了TAT - 59（米普昔芬）的I期研究。TAT - 59是日本研发的一种用于乳腺癌的抗雌激素药物。口服给予单次剂量1.25、5、10、20、40和80毫克，或连续5天每日剂量1.25、5、10、20和40毫克。单次给药后，未发现临床不良反应。一名患者在单次服用5毫克TAT后，出现血清钠、氯、钙水平降低以及血清乳酸脱氢酶（LDH）水平升高。一名患者在单次服用10毫克TAT后，也观察到血清LDH水平升高。一名患者在单次服用40毫克TAT后，分别出现血清LDH水平和总胆红素升高、嗜酸性粒细胞增多、血钾升高以及血清呈乳糜状。所有这些异常值在最后一次给予TAT后26天内恢复到正常水平。连续给予TAT后，未观察到不良临床发现和异常实验室检查结果。餐后单次给药后，TAT的去磷酸化代谢产物DP - TAT及其去甲基化代谢产物DMDP达到最大血清浓度（Tmax）的时间分别为5.0至7.3小时和17.0至42.8小时。DP和DMDP的最大血清浓度（Cmax）和药时曲线下面积（AUC）呈剂量依赖性升高。DP和DMDP的半衰期（T1/2）分别为24.2至41.5小时和91.9至214.7小时。进食前后TAT的药代动力学无显著差异。基于上述结果，我们得出结论，应开展II期研究以评估TAT的疗效、安全性和最佳剂量。
