title: Oral follicle-stimulating hormone agonist tested in healthy young women of reproductive age failed to demonstrate effect on follicular development but affected thyroid function.
abstract: OBJECTIVE
  To assess the safety, pharmacokinetics, and pharmacodynamics of MK-8389.
  
  
  METHODS
  Double-blind, placebo-controlled, parallel-group, ascending dose study.
  
  
  METHODS
  Two clinical research organizations.
  
  
  METHODS
  Healthy young women.
  
  
  METHODS
  Once-daily oral doses of MK-8389 or placebo for 14 days.
  
  
  METHODS
  Safety, including thyroid function tests (TFTs), pharmacokinetics, and follicular development (follicle size and number and serum E2 and inhibin B levels).
  
  
  RESULTS
  Treatment with MK-8389 was generally safe and well tolerated. An effect on TFTs was observed, which was transient and did not lead to clinical signs or symptoms but prevented dose escalation above 40 mg. MK-8389 was rapidly absorbed, slowly eliminated, and showed a large peak-to-trough ratio. No clinically meaningful effect was seen on follicle size and numbers, which was consistent with the low E2 levels. At doses >20 mg, inhibin B levels were increased, suggesting early follicular development at higher doses.
  
  
  CONCLUSIONS
  Oral administration of MK-8389 demonstrated acceptable systemic exposure and was generally well tolerated. This study failed to demonstrate a clinically meaningful effect of MK-8389 on follicular development, whereas MK-8389 unexpectedly affected thyroid function. This study did not explore doses above 40 mg given the changes observed in TFTs, which may relate to high MK-8389 peak concentrations.
  
  
  BACKGROUND
  EudraCT Number 2010-022396-57.
authors.affiliation: MSD Netherlands, Oss, the Netherlands; Merck & Co., Inc., Kenilworth, New Jersey. Electronic address: mireille.gerrits@merck.com.
authors.forename: Mireille G F
authors.initials: MG
authors.lastname: Gerrits
authors.affiliation: MSD Netherlands, Oss, the Netherlands.
authors.forename: Hester
authors.initials: H
authors.lastname: Kramer
authors.affiliation: MSD Netherlands, Oss, the Netherlands.
authors.forename: Rachid
authors.initials: R
authors.lastname: el Galta
authors.affiliation: MSD Netherlands, Oss, the Netherlands.
authors.forename: Geertje
authors.initials: G
authors.lastname: van Beerendonk
authors.affiliation: MSD Netherlands, Oss, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Hanssen
authors.affiliation: QPS, Groningen, the Netherlands.
authors.forename: Khalid
authors.initials: K
authors.lastname: Abd-Elaziz
authors.affiliation: Dinox, Groningen, the Netherlands.
authors.forename: Christine
authors.initials: C
authors.lastname: Klipping
authors.affiliation: Dinox, Groningen, the Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Duijkers
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
mesh_terms: D000284:Administration, Oral; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005640:Follicle Stimulating Hormone / Q000008:administration & dosage / Q000819:agonists* / Q000031:analogs & derivatives*; D006801:Humans; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development*; D012098:Reproduction / Q000187:drug effects / Q000502:physiology*; D013961:Thyroid Gland / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005640:Follicle Stimulating Hormone
keywords: Follicular development; follicle-stimulating hormone; infertility; oral FSH agonist