REPRODUCTIVE ENDOCRINOLOGY

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1 FERTILITY AND STERILITY VOL. 72, NO. 6, DECEMBER 1999 Copyright 1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. REPRODUCTIVE ENDOCRINOLOGY Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran*). Part I. Absolute bioavailability of 0.25 mg of ganirelix after a single subcutaneous injection in healthy female volunteers Janine J. L. Oberyé, M.Sc., Bernadette M. J. L. Mannaerts, M.Sc., Huub-Jan Kleijn, B.Sc., and Cees J. Timmer, M.Sc. Research and Development, NV Organon, Oss, the Netherlands Received March 24, 1999; revised and accepted July 7, Supported by NV Organon, Oss, the Netherlands. Presented at the 5th International Symposium on GnRH Analogues in Cancer and Human Reproduction, Geneva, Switzerland, February 4 7, Reprint requests: Janine J. L. Oberyé, M.Sc., Research and Development, NV Organon, Post Office Box 20, 5340 BH, Oss, the Netherlands (FAX: ; j.oberye@organon.oss.akzonobel.nl). * Orgalutran, NV Organon, Oss, the Netherlands /99/$20.00 PII S (99) Objective: To assess the absolute bioavailability of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands) after a single SC injection. Design: Randomized, crossover, pharmacokinetic study. Setting: Phase I clinical research unit. Patient(s): Nineteen healthy female volunteers of reproductive age. Intervention(s): Two separate injections of 0.25 mg of ganirelix were given, one subcutaneously and one intravenously, with a washout period of 1 week between injections. Blood samples were taken for assessment of serum ganirelix concentrations, and blood pressure, heart rate, and adverse events were monitored. Main Outcome Measure(s): Pharmacokinetic parameters. Result(s): Fifteen subjects were evaluated. The mean concentration-time profile after SC administration was comparable to that after IV administration. The mean ( SD) peak concentration and time of occurrence after SC administration were ng/ml and hours, respectively. The mean ( SD) half-lives after IV administration and SC administration were highly similar ( hours and hours, respectively). Mean ( SD) AUC 0 (area under the concentration-time curve) values of ng/ml hours and ng/ml hours were calculated for IV administration and SC administration, respectively, resulting in an absolute mean ( SD) bioavailability of 91.3% 6.7%. Both treatments were well tolerated. Conclusion(s): Ganirelix is absorbed rapidly and extensively after SC administration, resulting in a high absolute bioavailability of 90%. (Fertil Steril 1999;72: by American Society for Reproductive Medicine.) Key Words: GnRH antagonist, ganirelix, absolute bioavailability, pharmacokinetics, intravenous, subcutaneous Gonadotropin-releasing hormone analogues are used for a variety of disorders in which reversible suppression of the pituitary-gonadal axis is desired (1). Gonadotropin-releasing hormone agonists are used to treat endometriosis, uterine fibroids, precocious puberty, and prostatic hyperplasia, and to prevent premature LH surges during controlled ovarian hyperstimulation (COH). Gonadotropin-releasing hormone agonists act through desensitization of the receptor, which eventually results in receptor down-regulation. However, this mechanism of action initially leads to an increased release of gonadrotropins (flare-up), which generally is considered to be a disadvantage of their use, especially for short-term indications in which rapid pituitary suppression is required. Gonadotropin-releasing hormone antagonists act by a completely different mechanism. They block the GnRH receptor by binding to the receptor without activating it, which eventually results in a decrease in levels of LH and 1001

2 FSH. To be efficacious, they have to compete for the binding site with native GnRH, which normally initiates the release of LH and FSH. As a consequence, GnRH antagonists must be present at the receptor site continuously to displace native GnRH. Thus, a thorough understanding of the pharmacokinetic characteristics of a GnRH antagonist is of primary importance in establishing the optimal dosing regimen and anticipating the consequences of inadequate compliance or alterations in dosage or dosing. The third-generation GnRH antagonist ganirelix (Antagon/ Orgalutran; NV Organon, Oss, the Netherlands) is a decapeptide derived from native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, 8, and 10. It was developed for the prevention of premature LH rises in women undergoing COH. Recently published data from a dosefinding study (2) indicated that a once-daily SC dose of 0.25 mg, starting on day 6 of FSH stimulation, effectively prevented the occurrence of premature LH rises and resulted in a good ongoing pregnancy rate (33.8% per attempt; n 68). Previous reports on the pharmacokinetics of ganirelix are of limited relevance to women undergoing COH, as these trials were designed to evaluate the efficacy and safety of ganirelix for the long-term suppression of gonadotropins. Toward this end, the studies were conducted in men (3) and postmenopausal women (4) and generally involved higher doses of ganirelix (4, 5) or a different route of administration (6). Therefore, the present study aimed to describe the pharmacokinetic characteristics of a single dose of 0.25 mg of ganirelix given subcutaneously to women of reproductive age, who are representative of the patients who undergo COH. MATERIALS AND METHODS Volunteers A total of 19 healthy female volunteers were screened and considered eligible to participate in the study. All women were in good physical condition and had been taking oral contraceptives for at least 3 months. Volunteers with a history of or current type I hypersensitivity (e.g., urticaria, eczema, hay fever, and asthma) were excluded from participation. All subjects gave their written informed consent and agreed to use nonhormonal contraceptive methods during the study. Study Design This study was an open-label, randomized, crossover, single-dose, pharmacokinetic study. The study was approved by the ethics committee of the clinical research unit and was performed in accordance with the latest revision of the Declaration of Helsinki. After screening and acceptance into the study, the volunteers discontinued the daily intake of contraceptive pills exactly 1 week before the first drug injection. After this pill-free period, the volunteers were randomized to one of two treatment sequences: SC injection followed by IV injection, or the reverse. They received a single SC injection and a single IV injection of 0.25 mg of ganirelix (Org 37462, Antagon/Orgalutran) in the predetermined order, with a washout period of 1 week between injections. The SC injection was given in the upper leg and the IV injection was given in the arm. During each treatment period, the volunteers were hospitalized from the day before the administration of the drug until 24 hours after the injection. They were instructed to remain in a semirecumbent position until at least 2 hours after each injection. Assessments Blood samples for the assessment of serum ganirelix levels were drawn just before and at 0.08 (IV only), 0.17 (IV only), 0.25, 0.33 (IV only), 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after each injection. Blood samples were processed to serum immediately after collection and stored at 20 C until analysis. For the safety evaluation, systolic and diastolic blood pressure and heart rate were assessed just before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after drug administration. In addition, adverse events were monitored. Assay For quantification of serum ganirelix concentrations, a validated RIA without prior sample purification was used as previously described by Nerenberg et al. (7). The lower limit of quantification for this assay was 0.02 ng/ml. Calibration curves in the range of ng/ml were linear, with correlation coefficients of at least Quality control (QC) samples, consisting of human serum spiked with ganirelix at nominal levels of 0.06 ng/ml (low QC), 0.3 ng/ml (mid- QC), 0.8 ng/ml (high QC), and 50 ng/ml (over the curve QC) were analyzed in each analysis series. The intraassay and interassay coefficients of variation ranged from 3.6% 6.2% and from 3.9% 12.3%, respectively. Analysis Pharmacokinetics Four volunteers were excluded from the pharmacokinetic analysis: one failed to take adequate contraceptive measures, one received an incomplete IV injection, and two violated the exclusion criterion of type I hypersensitivity. Of the last two subjects, one had eczema, which worsened after the SC ganirelix injection. The other subject had a history of hay fever but tolerated the SC ganirelix injection well, without any symptoms. Nevertheless, both subjects violated the exclusion criteria and were withdrawn after the first treatment period. For the remaining 15 subjects, the following parameters were calculated from the ganirelix serum concentrations: 1. C max and t max (SC administration only): the peak concentration and the time of its occurrence were taken from the measured serum level data. 2. k el and t 1/2 : from the individual log concentration versus time plots, it was determined by visual inspection from which 1002 Oberyé et al. Ganirelix absolute bioavailability study Vol. 72, No. 6, December 1999

3 TABLE 1 Demographic characteristics of 19 healthy female volunteers who received at least one ganirelix injection. Characteristic Mean SD Minimum Median Maximum FIGURE 1 Log-linear plot of serum ganirelix concentrations after SC administration and IV administration of 0.25 mg of ganirelix to 15 healthy female volunteers. Age (y) Height (cm) Weight (kg) BMI (kg/m 2 ) Note: BMI body mass index. time onward to the last time point, the concentration versus time (C-t) plot was approximately linear. Using log-linear regression on these terminal data points of the C-t curve, the slope (k el ) was estimated; the elimination half-life (t 1/2 ) was calculated as e log(2)/k el. Concentrations lower than the detection limit in the elimination phase were ignored. 3. AUC 0 tfix : the area under the C-t curve from zero to tfix was calculated with the use of the linear trapezoidal rule, where tfix represents the last time point for which all subjects had measurable concentrations. 4. AUC 0 : the area under the C-t curve from zero to infinity was calculated as AUC 0 tz AUC tz, where tz is the sampling time point of the last measurable concentration per individual subject. AUC 0 tz was calculated with the use of the linear trapezoidal rule, and AUC tz was calculated as C tz /k el, where C tz is the best fitted concentration at time tz. In case of a value lower than the detection limit, a concentration of zero was assumed. 5. F: the individual bioavailability was calculated as the ratio of the AUC 0 after SC and IV administration. 6. CL (IV administration only): the total serum clearance was calculated as dose/auc V d (IV administration only): the volume of distribution during the terminal phase was defined as CL/k el. Absolute Bioavailability The absolute bioavailability of the drug after SC administration was estimated as the ratio of the least-squares geometric means of the AUC 0 values after IV administration and SC administration (SC administration divided by IV administration). This estimate and the corresponding 95% confidence intervals were obtained using an analysis of variance on logarithmically transformed values. The analysis of variance model comprised the following factors: subject (sequence), sequence, period, and treatment. RESULTS Volunteers Demographic data on all subjects are presented in Table 1. In summary, 19 healthy women, ranging in age from years, received at least one ganirelix injection. The women had an average weight of 63.1 kg and a mean body mass index of 21.7 kg/m 2. The demographic characteristics of all subjects who received a ganirelix injection were comparable to those of the 15 subjects who eventually were included in the pharmacokinetic evaluation (data not shown). Pharmacokinetics Evaluation of the pharmacokinetic results revealed that there was no sequence effect. The mean serum concentration versus time curves after single SC and IV injections of 0.25 mg of ganirelix are presented in Figure 1. After SC administration, absorption appeared to be rapid and almost complete, as peak concentrations were reached after 1 hour (t max ). Further, the ganirelix levels measured at 2 hours after SC administration approximated those measured after IV administration. Thereafter, concentrations after SC injection declined at the same rate as concentrations after IV injection. Altogether, the similarity of the concentration-time profiles indicates that the systemic exposure to ganirelix after IV administration and SC administration was comparable. This finding was substantiated by the corresponding pharmacokinetic parameters, which are presented in Table 2. After SC administration, peak serum levels of ganirelix averaged 14.8 ng/ml and were reached after 1.1 hours. The mean total clearance and volume of distribution of ganirelix were calculated after IV administration and appeared to be 2.4 L/h and 43.7 L, respectively. The mean half-lives after FERTILITY & STERILITY 1003

4 TABLE 2 Summary of pharmacokinetic parameters and bioavailability results calculated from serum ganirelix concentrations measured after IV and SC administration of 0.25 mg of ganirelix to 15 healthy female volunteers. FIGURE 2 Systolic and diastolic blood pressure after SC administration (n 18) and IV administration (n 17) of 0.25 mg of ganirelix to healthy female volunteers. Œ systolic (IV); systolic (SC); F diastolic (IV); E diastolic (SC). Route of administration Pharmacokinetic parameter IV SC C max (ng/ml) t max (h) Clearance (L/h) Volume of distribution (L) Elimination half-life (h) AUC 0 48 (ng/ml hours) AUC 0 (ng/ml hours) Absolute bioavailability (%) Note: Values are means SD. C max peak concentration; t max time point of occurrence of peak concentration; AUC 0 48 area under the concentration versus time curve from 0 48 hours after dosing; AUC 0 area under the concentration versus time curve from zero to infinity. SC administration and IV administration were highly similar (12.8 hours and 12.7 hours, respectively). The area under the concentration-time curves up to infinity averaged 96 ng/ml hours and 105 ng/ml hours after SC administration and IV administration, respectively. The absolute bioavailability was calculated to be 91%, with the 95% confidence interval ranging from Safety Both SC and IV injection were well tolerated. No serious adverse events occurred, and most reported adverse events were of a mild intensity. The most frequently reported side effects included injection site reactions (eight subjects), headache (7 subjects), and fatigue (7 subjects). Local reactions at the injection site were reported primarily after SC injection, whereas no difference in the incidence of headache and fatigue was observed between the two treatments. All reactions at the injection site were of mild intensity and generally disappeared within 24 hours after injection. The results of the systolic and diastolic blood pressure readings are depicted in Figure 2. No difference in blood pressure was observed after the two treatments. A temporary decrease in systolic and diastolic blood pressure of approximately 10 mm Hg was observed during the first 2 hours after both routes of administration, when the volunteers were instructed to remain in a semirecumbent position. DISCUSSION To be systemically active, drugs administered subcutaneously have to be absorbed from the injection site into the general circulation. Delays in absorption or losses at the injection site often result in a lower or extremely variable pharmacodynamic response. Further, the reversibility of the effect can be impaired. Especially for short-acting GnRH antagonists, drug absorption from the SC tissue should be rapid and complete, without gelling. The absorption process depends mainly on the structure and thereby on the physicochemical properties of the compound. Because ganirelix has a high solubility and several hydrophobic sites, rapid and extensive absorption can be expected. The high absolute bioavailability ( 90%) observed in the current study confirms these properties of the compound. For cetrorelix, another GnRH antagonist that is being developed for the same indication, a lower absolute bioavailability of 85% was reported (8). In addition to assessing the absolute bioavailability, the present study is the first one to describe the pharmacokinetic characteristics of a single dose of 0.25 mg of ganirelix given subcutaneously to women of reproductive age. Overall, the individual concentration-time profiles were comparable and indicated low intersubject variability. This also was reflected in the low coefficient of variation (10% 34%) for the main pharmacokinetic parameters. The average concentrationtime profile after SC injection was similar to that after IV injection. Evaluation of the concentrations measured during the elimination phase revealed two parallel lines, indicating that serum concentrations declined at the same rate after both injection methods. This was reflected in the elimination 1004 Oberyé et al. Ganirelix absolute bioavailability study Vol. 72, No. 6, December 1999

5 half-lives, which were virtually identical, implying that elimination is not limited by the rate of absorption and that it is unlikely that depot formation or gelling occurred at the SC injection site. The rapid absorption, as illustrated by the occurrence of C max at 1 hour after injection, is in line with previous reports on other GnRH antagonists such as Nal-Glu (9) and cetrorelix (8, 10, 11). In contrast, the elimination half-life seemed to differ with the compound used and to depend on the dose and route of administration. After SC administration of 5 mg of Nal-Glu to men, an elimination half-life of hours was reported (9), which corresponds with the half-life of ganirelix. For cetrorelix, half-lives of 11 hours and 12 hours were reported after IV administration of 3 mg to women and men, respectively, whereas much longer half-lives of 25 hours and 37 hours, respectively, were obtained when the same dosages were given subcutaneously (8). Ongoing absorption from a depot at the injection site probably causes this discrepancy. Most likely, this depot formation and the consequently slow elimination of cetrorelix occurs when higher dosages are used, as half-lives of 5 10 hours were reported after the administration of dosages of up to 1 mg (10) but half-lives of 30 hours were reported after the SC injection of 5 mg (11). It is known that GnRH antagonists of the previous generation can cause mast cell degranulation on contact (12). However, in studies of SC ganirelix administration, the compound has been shown to have only minimal histaminereleasing properties (2, 4, 5). The present study demonstrated that ganirelix also is well tolerated after IV administration. No apparent difference in the incidence of adverse events or in the effect on blood pressure was observed between the SC and IV routes of administration. The small, temporary decrease in systolic and diastolic blood pressure seen during the first 2 hours after each type of injection most likely was due to the semirecumbent position of the subjects during this period. Overall, the safety data suggest that there is no need for specific concern in case of accidental IV administration. In summary, this study demonstrated that ganirelix is absorbed rapidly and extensively after SC administration, resulting in a high absolute bioavailability of 90%. Further, it confirmed that both SC and IV administration of ganirelix are safe and well tolerated. Acknowledgments: The authors thank the involved members of the staff of Pharma Bio-Research International B.V., Zuidlaren, the Netherlands, for their assistance during the conduct and evaluation of the trial. References 1. Conn PM, Crowley WF. Gonadotropin-releasing hormone and its analogs. Annu Rev Med 1994;45: The Ganirelix Dose-finding Study Group. A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum Reprod 1998;13: Shah J, Monroe S, Wolfe L, LaFargue J, Pavlou S. Pharmacokinetics and pharmacodynamics of a novel GnRH antagonist (RS-26306) in humans [abstract]. Pharm Res 1991;8(Suppl):S Rabinovici J, Rothman P, Monroe SE, Nerenberg C, Jaffe RB. Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (ganirelix) with minimal histamine-releasing properties: studies in post-menopausal women. J Clin Endocrinol Metab 1992;75: Nelson LR, Fuijimoto VY, Jaffe RB, Monroe SE. Suppression of follicular phase pituitary-gonadal function by a potent new gonadotropin-releasing hormone antagonist with reduced histamine-releasing properties (ganirelix). Fertil Steril 1995;63: Fuijimoto VY, Monroe SE, Nelson LR, Downey D, Jaffe RB. Doserelated suppression of serum luteinizing hormone in women by a potent new gonadotropin-releasing hormone antagonist (ganirelix) administered by intranasal spray. Fertil Steril 1997;67: Nerenberg C, LaFargue J, Gee C, Chu F, Wolfe L, Chan R, et al. Radioimmunoassay of ganirelix in plasma or serum. J Immunoassay 1993;14: Hermann R, Romeis P, Schneider E, Ellers-Lenz B, Ruus P, Reissmann T, et al. Pharmacokinetics and absolute bioavailability of the LHRHantagonist cetrorelix in healthy male and female subjects [abstract]. Eur J Clin Pharmacol 1995;40:A Pavlou SN, Wakefield G, Schlechter NL, Lindner J, Souza KH, Kamilaris CT, et al. Mode of suppression of pituitary and gonadal function after acute or prolonged administration of a luteinizing hormone-releasing antagonist in normal men. J Clin Endocrinol Metab 1989;68: Duijkers IJM, Klipping C, Willemsen WNP, Krone D, Schneider E, Niebch G, et al. Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist cetrorelix in healthy female volunteers. Hum Reprod 1998;13: Behre HM, Klein B, Steinmeyer E, McGregor GP, Voigt K, Nieschlag E. Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist cetrorelix (SB-75) in normal men. J Clin Endocrinol Metab 1992;75: Morgan JE, O Neil CE, Coy DH, Hocart SJ, Nekola MV. Antagonistic analogs of luteinizing hormone-releasing hormone are mast cell secretagogues. Int Arch Allergy Appl Immunol 1986;80:70 5. FERTILITY & STERILITY 1005

Orgalutran 0.25 mg/0.5 ml solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Orgalutran 0.25 mg/0.5 ml solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 1. NAME OF THE MEDICINAL PRODUCT 0.25 mg/0.5 ml solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each pre-filled syringe contains 0.25 mg of ganirelix (INN) in 0.5 mg aqueous solution.