Pharmacologic profiling of corifollitropin alfa, the first developed sustained follicle stimulant.
Corifollitropin alfa (Elonva®, MSD, previously N.V. Organon or Schering-Plough Oss, The Netherlands) is a newly developed sustained follicle stimulant composed of the α subunit of human follicle-stimulating hormone (FSH) and a hybrid β subunit formed by fusion of the human chorionic gonadotropin β subunit carboxy terminal peptide with the β subunit of human FSH. Binding characteristics of corifollitropin alfa at the rat FSH receptor and transactivation properties at the rat FSH receptor, human luteinizing hormone (LH) receptor, and human thyroid-stimulating hormone receptor (TSH receptor) were assessed in vitro. Bioactivity of corifollitropin alfa in rats was also assessed. Serum corifollitropin alfa levels in rats and dogs were used to derive the main pharmacokinetic parameters of corifollitropin alfa. Binding and transactivation profile of corifollitropin alfa to rat FSH receptor was specific and comparable to that of recombinant human FSH, with no intrinsic TSH receptor or LH receptor activation. From pharmacokinetic studies, circulating half-life of corifollitropin alfa was calculated to be 17.3h in rats and 46.9h in dogs, 1.5- to 2-fold longer than recombinant FSH. Corifollitropin alfa demonstrated a 2- to 4-fold increase in bioactivity (ovarian weight, serum estradiol and progesterone, ovulated ova) over recombinant FSH across all in vivo parameters assessed. These data demonstrate that corifollitropin alfa is a specific ligand with high affinity for FSH receptor, lacking intrinsic activity for LH receptor and TSH receptor. By virtue of its increased in vivo half-life, corifollitropin alfa can be a valuable alternative to FSH by acting as a sustained follicle stimulant.
Department of Pharmacology, Merck, Sharpe and Dohme MSD, 5340 BH Oss, The Netherlands.
Pieter
P
Verbost
Willem N
WN
Sloot
Ursula M
UM
Rose
Renato
R
de Leeuw
Rob G J M
RG
Hanssen
Gijs F M
GF
Verheijden
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D055808:Drug Discovery; D004958:Estradiol / Q000097:blood; D005260:Female; D043373:Follicle Stimulating Hormone, Human / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000033:anatomy & histology / Q000187:drug effects; D011374:Progesterone / Q000097:blood; D051381:Rats; D011962:Receptors, FSH / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects
D043373:Follicle Stimulating Hormone, Human; D011962:Receptors, FSH; C437186:follicle stimulating hormone, human, with HCG C-terminal peptide; D011374:Progesterone; D004958:Estradiol