Pechstein B, Nagaraja N V, Hermann R, Romeis P, Locher M, Derendorf H
Department of Biological Research Biochemistry, ASTA Medica AG, Frankfurt, Germany.
J Clin Pharmacol. 2000 Mar;40(3):266-74. doi: 10.1177/00912700022008937.
Cetrorelix (CET), a potent luteinizing hormone-releasing hormone (LH-RH) antagonist, was recently approved for the prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oocyte pickup and assisted reproductive techniques (ART), and is currently under clinical trials for benign prostate hyperplasia, endometriosis, and tumors sensitive to sex hormones. CET suppresses luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) in men. The purpose of this study was to evaluate the pharmacokinetics and absolute bioavailability of 3 mg intravenously and subcutaneously administered CET in healthy male and female volunteers and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to link the plasma concentrations of CET to the T and LH suppression in males. Following intravenous (IV) (n = 5) and subcutaneous (SC) (n = 6) administration of CET acetate, CET and hormone plasma levels were measured by radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods, respectively. Pharmacokinetics of CET was explained by a three-compartment model for the IV route and by a two-compartment model with first-order absorption for the SC route. Average absolute bioavailability after SC administration was 85%. There were no differences in the pharmacokinetics between male and female subjects (ANOVA, p > 0.05). Single IV and SC doses of CET caused immediate and distinct suppression of LH, FSH, and T levels by 80%, 45% and 95% of their baseline levels, respectively. The duration of hormone suppression was longer for the SC route. An indirect-response PK-PD Emax model was developed to link the measured CET plasma concentrations with the respective T or LH levels. In addition, the circadian rhythm of T levels was accounted by including a cosine function in a second separate PD model. The PD model with cosine function was applied to T baseline levels as well as to the suppressed concentrations after CET dosing. The two models adequately described the PK-PD relationship between plasma levels of CET and T suppression following IV and SC dosing. The EC50 values (mean +/- SD) for the suppression of T were similar (p > 0.05) between the two routes of administration and the two models.
西曲瑞克（CET）是一种强效的促黄体生成激素释放激素（LH-RH）拮抗剂，最近被批准用于预防接受控制性卵巢刺激（COS）、随后进行卵母细胞采集和辅助生殖技术（ART）的患者过早排卵，目前正在进行治疗良性前列腺增生、子宫内膜异位症和对性激素敏感肿瘤的临床试验。CET可抑制男性体内的促黄体生成激素（LH）、促卵泡生成激素（FSH）和睾酮（T）。本研究的目的是评估3mg静脉注射和皮下注射CET在健康男性和女性志愿者中的药代动力学和绝对生物利用度，并建立一个药代动力学-药效学（PK-PD）模型，将CET的血浆浓度与男性体内T和LH的抑制联系起来。静脉注射（IV）（n = 5）和皮下注射（SC）（n = 6）醋酸西曲瑞克后，分别采用放射免疫分析（RIA）和酶免疫分析（EIA）方法测定CET和激素的血浆水平。静脉注射途径的CET药代动力学用三室模型解释，皮下注射途径用具有一级吸收的二室模型解释。皮下注射后的平均绝对生物利用度为85%。男性和女性受试者的药代动力学无差异（方差分析，p > 0.05）。单次静脉注射和皮下注射CET分别使LH、FSH和T水平立即且明显抑制至其基线水平的80%、45%和95%。皮下注射途径的激素抑制持续时间更长。建立了一个间接反应PK-PD Emax模型，将测得的CET血浆浓度与各自的T或LH水平联系起来。此外，通过在第二个单独的PD模型中纳入余弦函数来考虑T水平的昼夜节律。带有余弦函数的PD模型应用于T基线水平以及CET给药后的抑制浓度。这两个模型充分描述了静脉注射和皮下注射给药后CET血浆水平与T抑制之间的PK-PD关系。两种给药途径和两种模型之间，T抑制的EC50值（平均值±标准差）相似（p > 0.05）。
