Pharmacokinetic-pharmacodynamic modeling of testosterone and luteinizing hormone suppression by cetrorelix in healthy volunteers

Cetrorelix (CET), a potent luteinizing hormone-releasing hormone (LH-RH) an tagonist was recently approved for the prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oo cyte pickup and assisted reproductive techniques (ART), end is currently un der clinical trials for benign prostate hyperplasia, endometriosis, and tu mors sensitive to sex hormones. CET suppresses luteinizing hormone (LH), fo llicle-stimulating hormone (FSH), and testosterone (T) in men. The purpose of this study was to evaluate the pharmacokinetics and absolute bioavailabi lity of 3 mg intravenously and subcutaneously administered CET in healthy m ale and female volunteers and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to Link the plasma concentrations of CET to the T and LH supp ression in males. Following intravenous (IV) (n = 5) and subcutaneous (SC) (n = 6) administration of CET acetate, CET and hormone plasma levels were m easured by radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods, res pectively. Pharmacokinetics of CET was explained by a three-compartment mod el far the IV route and by a two-compartment model with first-order absorpt ion for the SC route. Average absolute bioavailability after SC administrat ion was 85%. There were no differences in the pharmacokinetics between male and female subjects (ANOVA, p > 0.05). Single Nand 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 suppre ssion was longer for the SC route, An indirect-response PK-PD E-max model w as developed to link the measured CET plasma concentrations with the respec tive T or LH levels. in addition, the circadian rhythm of T levels wets acc ounted 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 t he suppressed concentrations after CET dosing. The two models adequately de scribed the PK-PD relationship between plasma levels of CET and T suppressi on following Nand SC dosing. The EC50 values (mean +/- SD) for the suppress ion of T were similar (p > 0.05) between the two routes of administration a nd the two models. (C) 2000 the American College of Clinical Pharmacology.