Phase I and clinical pharmacology of a type I and II, 5-alpha-reductase inhibitor (LY320236) in prostate cancer: Elevation of estradiol as possible mechanism of action
Phase I and clinical pharmacology of a type I and II, 5-alpha-reductase inhibitor (LY320236) in prostate cancer: Elevation of estradiol as possible mechanism of action
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DOI：
10.1016/j.urology.2003.08.017
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发表时间：
2004-01-01
期刊：
影响因子：
2.1
通讯作者：
Raghavan, D
中科院分区：
文献类型：
--
作者：
Eisenberger, MA;Laufer, M;Raghavan, D
目标.目的研究双特异性5-α-还原酶抑制剂（LY 320236）治疗前列腺癌的安全性、药代动力学、生物学活性和初步疗效。51例复发性或转移性前列腺癌患者按顺序（非随机）分配至队列中，接受5种每日单次口服剂量的LY 320236（10、50、150、250和500 mg）。系列评价包括第1、29和57天的血清睾酮、双氢睾酮、雄烯二醇葡糖苷酸、雌二醇和药代动力学。定期进行毒性评估、X线/扫描和血液检查，包括血清前列腺特异性抗原（PSA）测定。总体而言，治疗耐受性良好，51例患者中有3例发生可逆的3-4级毒性（1例腹泻，2例肝酶升高）。150 mg或更高剂量组的血药峰浓度（给药后2 - 3小时）高于150 mg以下剂量组，且蓄积缓慢。治疗期间血清睾酮、双氢睾酮和雄烯二醇葡糖苷酸水平无显著变化;然而，去势组和非去势组的血清雌二醇水平均出现统计学显著性升高。基线PSA水平≥ 5 ng/mL的非去势组1/26例和去势组4/15例（27%）PSA下降≥ 50%持续4周或更长时间。LY 320236治疗与中度可逆毒性相关。在去势组和非去势组中均观察到雌二醇水平升高，但PSA下降主要见于去势组。没有心血管毒性表明，这种药物可能是一个有前途的替代外源性雌激素的前列腺癌患者谁表现出的证据后，初步雄激素剥夺治疗疾病进展。(C)2004爱思唯尔公司
Objectives. To study the safety, pharmacokinetics, biologic activity, and preliminary efficacy of the bispecific 5-alpha-reductase inhibitor (LY320236) in prostate cancer.Methods. Fifty-one patients with recurrent or metastatic prostate cancer were sequentially (nonrandomly) assigned in cohorts to receive one of five single daily oral doses of LY320236 (10, 50, 150, 250, and 500 mg). Serial evaluations included serum testosterone, dihydrotestosterone, androstenediol glucuronide, estradiol, and pharmacokinetics on days 1, 29, and 57. Toxicity assessments, x-rays/scans, and blood tests, including serum prostate-specific antigen (PSA) determination, were done at regular intervals.Results. Overall, treatment was well tolerated, with 3 of 51 patients developing reversible grade 3-4 toxicity (one diarrhea, two elevated liver enzymes). Peak blood levels (2 to 3 hours after drug administration) were greater for doses of 150 mg or greater compared with less than 150-mg doses with slow accumulation. Serum levels of testosterone, dihydrotestosterone, and androstenediol glucuronide did not change significantly during treatment; however, a statistically significant increase occurred in serum estradiol levels in both the castration and noncastration groups. One of 26 in the noncastration group and 4 (27%) of 15 in the castration group with baseline PSA levels of 5 ng/mL or greater had a 50% or greater PSA decline for 4 weeks orlonger.Conclusions. LY320236 treatment is associated with modest reversible toxicity. An elevation of estradiol levels was seen in both castration and noncastration groups, although PSA declines were primarily seen in the castration group. The absence of cardiovascular toxicity suggests that this agent may be a promising alternative to exogenous estrogens in patients with prostate cancer who demonstrate evidence of disease progression after initial androgen deprivation treatment. (C) 2004 Elsevier Inc.