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.
RCT Entities:
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.
Authors: Silvia Sposini; Francesco De Pascali; Rachel Richardson; Niamh S Sayers; David Perrais; Henry N Yu; Stephen Palmer; Selva Nataraja; Eric Reiter; Aylin C Hanyaloglu Journal: Front Pharmacol Date: 2020-11-30 Impact factor: 5.810