Oral follicle stimulating hormone agonist tested in healthy young women of reproductive age failed to demonstrate effect on follicular development but affected thyroid function

Capsule:
Oral administration of an FSH agonist demonstrated acceptable exposure and was well tolerated. No clear effect was observed on follicular development; higher doses were not tested owing to thyroid function test changes.

Authors:
Mireille G.F. Gerrits, Pharm.D., Hester Kramer, Ph.D., Rachid el Galta, Ph.D., Geertje van Beerendonk, Ph.D., Robert Hanssen, Ph.D., Khalid Abd-Elaziz, M.D., Christine Klipping, M.D., Ph.D., Ingrid Duijkers, M.D., Ph.D., S. Aubrey Stoch, M.D.

Volume 105, Issue 4, Pages 1056-1062

Abstract:

Objective:
To assess the safety, pharmacokinetics, and pharmacodynamics of MK-8389.

Design:
Double-blind, placebo-controlled, parallel-group, ascending dose study.

Setting:
Two clinical research organizations.

Patient(s):
Healthy young women.

Intervention(s):
Once-daily oral doses of MK-8389 or placebo for 14 days.

Main Outcome Measure(s):
Safety, including thyroid function tests (TFTs), pharmacokinetics, and follicular development (follicle size and number and serum E2 and inhibin B levels).

Result(s):
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.

Conclusion(s):
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.

Clinical Trial Registration Number:
EudraCT Number 2010-022396-57.

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