Single dose pharmacokinetics and effects on follicular growth and serum hormones of a long-acting recombinant FSH preparation (FSH-CTP) in healthy pituitary-suppressed females.
BACKGROUND
A long-acting FSH preparation has been developed by site-directed mutagenesis and gene transfer techniques.


METHODS
In this open-label trial, we investigated the pharmacokinetic and pharmacodynamic properties of FSH-CTP (corifollitropin alpha, Org 36286) in healthy female volunteers. Twenty-four subjects were treated with a high-dose oral contraceptive (OC) to suppress pituitary function. A single dose of 15, 30 or 60 micro g FSH-CTP was injected (s.c., eight subjects per dose group) and seven of these 24 subjects were subsequently treated with a single dose of 120 micro g.


RESULTS
Maximum serum FSH-CTP concentrations (0.42, 0.66, 1.49 and 3.27 ng/ml after administration of 15, 30, 60 and 120 micro g Org 36286 respectively) were reached between 36 and 48 h after injection and t(1/2) varied between 60 and 75 h. Dose proportionality was shown across the studied dose range, whereas t(max) and t(1/2) were dose independent. In most subjects follicular growth was observed; the number and maximum diameter of the follicles increased with the dose. Follicles with a diameter vertical line 8.0 mm were observed only in the 60 and 120 micro g dose groups, diameters between 12.0 and 15.9 mm occurred only in the 120 micro g group. Serum LH and 17beta-oestradiol levels remained low due to profound pituitary suppression whereas inhibin-B levels increased with dose. Maximum mean inhibin-B levels were 30.4, 322.7 and 1059.3 pg/ml in the 30, 60 and 120 micro g dose group respectively. The preparation was safe and well tolerated, and no FSH-CTP antibody formation was observed.


CONCLUSIONS
The pharmacokinetics of FSH-CTP were shown to be proportional with the dose. The elimination half-life was approximately two times longer than that of rFSH. A single dose of FSH-CTP was shown to be safe and able to induce multiple follicular growth accompanied by a dose-dependent rise in serum inhibin-B concentrations.
Duijkers
Ingrid J M
IJ
Dinox Medical Investigations, Groenewoudseweg 317, 6524 TX, Nijmegen, The Netherlands. dinox@molyvos.net
Klipping
Christine
C
Boerrigter
Peter J
PJ
Machielsen
Christel S M
CS
De Bie
Joris J
JJ
Voortman
Gerrit
G
D000328:Adult; D003276:Contraceptives, Oral / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D043373:Follicle Stimulating Hormone, Human; D006728:Hormones / Q000097:blood*; D006801:Humans; D007265:Inhibins / Q000097:blood; D006080:Ovarian Follicle / Q000187:drug effects* / Q000502:physiology*; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology; D012449:Safety
D003276:Contraceptives, Oral; D043373:Follicle Stimulating Hormone, Human; D006728:Hormones; C437186:follicle stimulating hormone, human, with HCG C-terminal peptide; C422364:inhibin B; D004958:Estradiol; D007265:Inhibins; D005640:Follicle Stimulating Hormone