madman
Super Moderator
Abstract
The purpose of this first-in-human trial was to examine the safety, pharmacokinetics, and pharmacodynamics of a novel recombinant human chorionic gonadotropin (FE 999302, choriogonadotropin beta) to support its clinical development for various therapeutic indications. The single and multiple-dose pharmacokinetics of choriogonadotropin beta (CG beta) were evaluated in women and the single-dose pharmacokinetics and pharmacodynamics of CG beta were compared to those of choriogonadotropin alfa (CG alfa) in men. CG beta was safe and well-tolerated in all 84 healthy subjects. In women, the area under the curve (AUC) and the peak serum concentration (Cmax) increased approximately dose proportionally following single and multiple doses of CG beta. The apparent clearance (CL/F) was approximately 0.5 L/h, the mean terminal half-life approximately 45 hours and the apparent distribution volume (Vz/F) approximately 30 L. After single administration in men, the mean AUC was 1.5-fold greater for CG beta than for CG alfa. Mean Cmax and Vz/F were comparable for the two preparations. In accordance with the differences in AUC, the CL/F was lower for CG beta (CL/F 0.5 vs 0.8 16 L/h), explained by a longer terminal half-life (47 vs 32 hours). Serum testosterone levels induced by a single dose rhCG reflected the pharmacokinetic profiles with a slight delay, resulting in 59% higher AUC for CG beta. The pharmacokinetic parameters for CG beta were comparable in men and in women. In conclusion, the pharmacokinetics differs between the two rhCG preparations, causing higher exposure and a higher pharmacodynamic response for CG beta, which may require relatively lower therapeutic doses.
Introduction
Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is produced by the pituitary in small amounts in non-pregnant women, men, and menopausal women whereas large amounts are produced by the placenta of pregnant women.1, 2 During early pregnancy, hCG is first expressed by the blastocyst before implantation and is increasingly produced after implantation by the syncytiotrophoblast. During the first trimester of pregnancy, hCG is produced in increasing amounts up to the 10th week of gestation and then decreases gradually.3 Since intact hCG is cleared by the kidneys, hCG may be isolated from the urine of women and used for the manufacturing of therapeutic preparations.4, 5
HCG consists of a 92 amino acid single α-subunit, which is common to all the pituitary glycoprotein hormones, and a specific β-subunit of 145 amino acids. Each subunit is post-translationally modified by the addition of complex carbohydrate moieties. The alpha subunit contains 2-N-linked glycosylation sites at amino acids 52 and 78 and the beta subunit contains 2-N-linked glycosylation sites at amino acids 13 and 30 and four O- linked glycosylation sites at amino acids 121, 127, 132 and 138.6, 7 HCG and luteinizing hormone (LH) show similar molecular structures and interact with the same LH/CG 11 receptor.8 As a result of this similarity to LH, hCG is used pharmacologically in a number of clinical indications. In women, hCG is used to induce final follicular maturation following controlled ovarian stimulation or to induce ovulation in anovulatory women.9 In men with hypogonadotropic hypogonadism, hCG is given to induce and maintain spermatogenesis.
To date, there is only one approved recombinant hCG (rhCG) preparation (choriogonadotropin alfa, CG alfa) which is expressed by a Chinese Hamster Ovary (CHO) cell-line and the pharmacokinetics are similar to those of urinary hCG.10, 11 Choriogonadotropin beta (CG beta, FE 999302) is a novel rhCG that has been produced by a human cell line (PER.C6©). The amino acid sequence of the α- and β-chains of CG beta are identical to those of endogenous hCG and CG alfa. Glycosylation of both natural and recombinant hCG is highly complex and may contain a wide range of structures.12 The glycosylation of recombinant hCG reflects the range of glycosyl-transferases present in the host cell line and is known to differ between rhCG products produced by different cell lines.13
PER.C6© and CHO cell lines are both used for the production of recombinant follicle-stimulating hormone (rFSH), with follitropin alfa expressed by a CHO cell line and follitropin delta expressed by the PER.C6© cell line. Investigations show that the preparations of rFSH from the PER.C6© human cell line and a CHO cell line display important differences in pharmacokinetic and pharmacodynamic properties.14 These differences include consistently higher exposure, longer time to Cmax, and longer t½ at steady state after repeated administrations, compared with follitropin alfa. A significantly lower clearance of follitropin delta compared with that of follitropin alfa was as well measured. Based on these differences which can be attributed to the glycosylation profile it may be anticipated that the pharmacokinetic and pharmacodynamic properties of rhCG expressed by a human cell line and by a CHO cell line will also be dissimilar.
To examine the safety, pharmacokinetics, and pharmacodynamics of CG beta, the first-in-human trial comprised three parts conducted sequentially and included healthy women using oral contraceptives and healthy men down-regulated with GnRH agonist. The single and multiple-dose pharmacokinetics of CG beta was first evaluated in healthy 10 women and then the single-dose pharmacokinetics and pharmacodynamics were compared to those of CG alfa in healthy men. The goal of this research was to establish the pharmacokinetics and pharmacodynamics of CG beta in women and men over a broad dose-range in order to allow further development of CG beta for any potential therapeutic indication.
Study Highlights
What is the current knowledge on the topic?
Recombinant hCG is indicated for the treatment of male or female infertility and administered by single or multiple subcutaneous injections.
What question did this study address?
A new recombinant hCG (choriogonadotropin beta) produced by a human-derived cell line (PER.C6) is currently in clinical development. The amino acid sequence of the α- and β-chains are identical to the natural sequences and also to that of rhCG expressed by CHO cell line (choriogonadotropin alfa), but the glycosylation provided by the PER.C6 and CHO cells are different. In this trial, the pharmacokinetics of choriogonadotropin beta were assessed in women and men and the pharmacokinetics and pharmacodynamics were compared in men to those of choriogonadotropin alfa.
What does this study add to our knowledge?
It is concluded that the pharmacokinetics of the two rhCG preparations are different, due to slower clearance of choriogonadotropin beta resulting in a higher pharmacodynamic response.
How might this change clinical pharmacology or translational science?
Further development of choriogonadotropin beta may require lower doses of this potent hCG compared to current therapeutic hCG preparations.
The purpose of this first-in-human trial was to examine the safety, pharmacokinetics, and pharmacodynamics of a novel recombinant human chorionic gonadotropin (FE 999302, choriogonadotropin beta) to support its clinical development for various therapeutic indications. The single and multiple-dose pharmacokinetics of choriogonadotropin beta (CG beta) were evaluated in women and the single-dose pharmacokinetics and pharmacodynamics of CG beta were compared to those of choriogonadotropin alfa (CG alfa) in men. CG beta was safe and well-tolerated in all 84 healthy subjects. In women, the area under the curve (AUC) and the peak serum concentration (Cmax) increased approximately dose proportionally following single and multiple doses of CG beta. The apparent clearance (CL/F) was approximately 0.5 L/h, the mean terminal half-life approximately 45 hours and the apparent distribution volume (Vz/F) approximately 30 L. After single administration in men, the mean AUC was 1.5-fold greater for CG beta than for CG alfa. Mean Cmax and Vz/F were comparable for the two preparations. In accordance with the differences in AUC, the CL/F was lower for CG beta (CL/F 0.5 vs 0.8 16 L/h), explained by a longer terminal half-life (47 vs 32 hours). Serum testosterone levels induced by a single dose rhCG reflected the pharmacokinetic profiles with a slight delay, resulting in 59% higher AUC for CG beta. The pharmacokinetic parameters for CG beta were comparable in men and in women. In conclusion, the pharmacokinetics differs between the two rhCG preparations, causing higher exposure and a higher pharmacodynamic response for CG beta, which may require relatively lower therapeutic doses.
Introduction
Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is produced by the pituitary in small amounts in non-pregnant women, men, and menopausal women whereas large amounts are produced by the placenta of pregnant women.1, 2 During early pregnancy, hCG is first expressed by the blastocyst before implantation and is increasingly produced after implantation by the syncytiotrophoblast. During the first trimester of pregnancy, hCG is produced in increasing amounts up to the 10th week of gestation and then decreases gradually.3 Since intact hCG is cleared by the kidneys, hCG may be isolated from the urine of women and used for the manufacturing of therapeutic preparations.4, 5
HCG consists of a 92 amino acid single α-subunit, which is common to all the pituitary glycoprotein hormones, and a specific β-subunit of 145 amino acids. Each subunit is post-translationally modified by the addition of complex carbohydrate moieties. The alpha subunit contains 2-N-linked glycosylation sites at amino acids 52 and 78 and the beta subunit contains 2-N-linked glycosylation sites at amino acids 13 and 30 and four O- linked glycosylation sites at amino acids 121, 127, 132 and 138.6, 7 HCG and luteinizing hormone (LH) show similar molecular structures and interact with the same LH/CG 11 receptor.8 As a result of this similarity to LH, hCG is used pharmacologically in a number of clinical indications. In women, hCG is used to induce final follicular maturation following controlled ovarian stimulation or to induce ovulation in anovulatory women.9 In men with hypogonadotropic hypogonadism, hCG is given to induce and maintain spermatogenesis.
To date, there is only one approved recombinant hCG (rhCG) preparation (choriogonadotropin alfa, CG alfa) which is expressed by a Chinese Hamster Ovary (CHO) cell-line and the pharmacokinetics are similar to those of urinary hCG.10, 11 Choriogonadotropin beta (CG beta, FE 999302) is a novel rhCG that has been produced by a human cell line (PER.C6©). The amino acid sequence of the α- and β-chains of CG beta are identical to those of endogenous hCG and CG alfa. Glycosylation of both natural and recombinant hCG is highly complex and may contain a wide range of structures.12 The glycosylation of recombinant hCG reflects the range of glycosyl-transferases present in the host cell line and is known to differ between rhCG products produced by different cell lines.13
PER.C6© and CHO cell lines are both used for the production of recombinant follicle-stimulating hormone (rFSH), with follitropin alfa expressed by a CHO cell line and follitropin delta expressed by the PER.C6© cell line. Investigations show that the preparations of rFSH from the PER.C6© human cell line and a CHO cell line display important differences in pharmacokinetic and pharmacodynamic properties.14 These differences include consistently higher exposure, longer time to Cmax, and longer t½ at steady state after repeated administrations, compared with follitropin alfa. A significantly lower clearance of follitropin delta compared with that of follitropin alfa was as well measured. Based on these differences which can be attributed to the glycosylation profile it may be anticipated that the pharmacokinetic and pharmacodynamic properties of rhCG expressed by a human cell line and by a CHO cell line will also be dissimilar.
To examine the safety, pharmacokinetics, and pharmacodynamics of CG beta, the first-in-human trial comprised three parts conducted sequentially and included healthy women using oral contraceptives and healthy men down-regulated with GnRH agonist. The single and multiple-dose pharmacokinetics of CG beta was first evaluated in healthy 10 women and then the single-dose pharmacokinetics and pharmacodynamics were compared to those of CG alfa in healthy men. The goal of this research was to establish the pharmacokinetics and pharmacodynamics of CG beta in women and men over a broad dose-range in order to allow further development of CG beta for any potential therapeutic indication.
Study Highlights
What is the current knowledge on the topic?
Recombinant hCG is indicated for the treatment of male or female infertility and administered by single or multiple subcutaneous injections.
What question did this study address?
A new recombinant hCG (choriogonadotropin beta) produced by a human-derived cell line (PER.C6) is currently in clinical development. The amino acid sequence of the α- and β-chains are identical to the natural sequences and also to that of rhCG expressed by CHO cell line (choriogonadotropin alfa), but the glycosylation provided by the PER.C6 and CHO cells are different. In this trial, the pharmacokinetics of choriogonadotropin beta were assessed in women and men and the pharmacokinetics and pharmacodynamics were compared in men to those of choriogonadotropin alfa.
What does this study add to our knowledge?
It is concluded that the pharmacokinetics of the two rhCG preparations are different, due to slower clearance of choriogonadotropin beta resulting in a higher pharmacodynamic response.
How might this change clinical pharmacology or translational science?
Further development of choriogonadotropin beta may require lower doses of this potent hCG compared to current therapeutic hCG preparations.
