Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects

Abstract

Background: Mifepristone is approved to control hyperglycemia in adults with endogenous
Cushing’s syndrome and is described as a mildly QTc prolonging drug, based on a TQT study.
The aim of the present study was to assess the effect of mifepristone on the QTc interval at plasma
mifepristone concentrations exceeding those observed in the TQT study.

Methods: Twenty healthy, male volunteers were given three doses of 1200 mg mifepristone
every 12 h with a high-fat meal in a randomized, placebo-controlled 2-period crossover study.
Holter ECG recordings were made on Day 1 and 2.

Results: Eighteen subjects completed the study. Mean peak plasma mifepristone concentrations
were 4.01 μg/mL (CV: 31%) on the fi rst dose and 5.77 μg/mL (CV: 29%) on the third
dose. Mifepristone did not have a meaningful QTc effect. The placebo-corrected, change-from-
-baseline QTcF (ΔΔQTcF) was between –1.6 and 0.7 ms on the fi rst dose (upper bound of 90%
CI 3.8 ms) and the largest ΔΔQTcF on the third dose was 4.9 ms (upper bound of 90% CI: 8.4 ms).
Concentration effect modeling showed a slightly negative slope of –0.01 ms/ng/mL.

Conclusions: Mifepristone did not cause a clinically meaningful QTc prolongation in healthy
volunteers at plasma concent rations of mifepristone and its main metabolites that clearly
exceeded those seen in a previous TQT study.