First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males
First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males
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DOI：
10.1093/humrep/16.8.1592
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发表时间：
2001-08-01
影响因子：
6.1
通讯作者：
Itskovitz-Eldor, J
中科院分区：
文献类型：
--
作者：
Bouloux, PMG;Handelsman, DJ;Itskovitz-Eldor, J
背景：这是人类首次接触到新型复合促卵泡激素-C端肽‘FSH-CTP’(Org 36286)，它是一种长效的重组FSH样物质，由人FSH的α-亚基和一个混合的β-亚基组成。后者由人FSH的β亚基和人绒毛膜促性腺激素(HCG)的β亚基的C末端部分(CTP)组成。方法：在这项I期非盲法多中心研究中，13名性腺功能减退的男性受试者入选，从人体抗体生成的角度测试FSH-CTP的安全性。此外，还测定了该新化合物的药代动力学曲线。受试者四次注射15杯FSH-CTP，每次注射的间隔类似于4周。结果：未发生与药物有关的(严重)不良事件。未检测到抗FSH-CTP和中国仓鼠卵巢(CHO)细胞来源蛋白的抗体，局部耐受性测定表明，S.C.FSH-CTP的给药耐受性良好，在重复暴露FSH-CTP后，注射部位的反应强度没有增加。分别于第一次和第三次注射后测定FSH-CTP血药浓度。总平均(+/-SD)Cmax为0.426(+/-0.116)ng/ml，平均T1/2为94.7(+/-2 6.2)h，AUC81.5(+/-18.8)ng·h/ml。与recFSH(Puregon(R))相比，FSH-CTP的半衰期增加了2-3倍。在第一次和第三次注射后，观察到血清抑制素-B浓度明显升高。结论：FSH-CTP的使用是安全的，不会导致可检测到的抗体形成。此外，FSH-CTP的药代动力学和动力学特征可能导致开发新的、更方便的治疗男性和女性不孕症的方案。
BACKGROUND: This is the first report of human exposure to the novel compound follicle stimulating hormone (FSH)-C-terminal peptide (CTP) 'FSH-CTP' (Org 36286), a long-acting recombinant FSH like substance, consisting of the alpha -subunit of human FSH and a hybrid beta -subunit. The latter is composed of the beta -subunit of human FSH and the C-terminus part (CTP) of the beta -subunit of human chorionic gonadotrophin (HCG). METHODS: In this phase I, non-blind, multi-centre study, 13 hypogonadotrophic hypogonadal male subjects were enrolled to test the safety of FSH-CTP in terms of antibody formation in humans. Furthermore, the pharmacokinetic profile of this new compound was determined. Subjects were injected four times with 15 mug FSH-CTP with an interval of similar to4 weeks between each injection. RESULTS: No drug related (serious) adverse events occurred. No antibodies against FSH-CTP or chinese hamster ovary (CHO)-cell derived proteins were detected and measurement of local tolerance demonstrated that s.c. administration of FSH-CTP is well tolerated and no increase in intensity of injection-site responses was observed after repeated exposure to FSH-CTP. After the first and third injection, FSH-CTP serum concentrations were determined. Overall mean (+/- SD) C-max was 0.426 (+/- 0.116) ng/ml, mean t1/2 and AUC(0-infinity) were 94.7 (+/- 26.2) h and 81.5 (+/- 18.8) ng.h/ml respectively. Compared with recFSH (Puregon (R)), the half life of FSH-CTP was increased 2-3 times. Following the first and third injection a clear rise in serum inhibin-B concentrations were observed. CONCLUSIONS: The use of FSH-CTP is safe and does not lead to detectable formation of antibodies. Furthermore, the pharmacokinetic and dynamic profile of FSH-CTP may lead to the development of new, more convenient regimens for the treatment of male and female infertility.