Clinical trials of potential new medicines must demonstrate cardiac safety. Regulatory guidelines require the analysis of high-quality electrocardiograms (ECGs) and blood concentration measurements to ensure the absence of an effect on the heart before a drug can be developed further. Richmond Research Institute, a world-class clinical research facility in London, specialises in essential clinical trial methodology studies. Here we present the results of our recent work on the cardiac safety of cortexolone 17α-propionate (cortexolone).
Cortexolone 7.5% solution, is a potent androgen receptor inhibitor being developed to treat alopecia (hair loss). The condition typically requires long-term use of medication applied to the scalp at home without medical supervision. Recent studies have demonstrated a weak inhibitory effect of cortexolone on hERG¹ potassium channels, suggesting the risk of cardiac toxicity is low. However, none of these studies were specifically designed to evaluate cardiac safety. Furthermore, given the potential for patients to apply cortexolone in excess of the recommended dose, examining its cardiac effects is essential.
The main aim of this study was to assess the effect of cortexolone on the QTc interval².
A total of 32 healthy men and women between 18 and 40 years of age took part in the study at our state-of-the-art clinical research facility at Richmond Pharmacology, London.
Cortexolone, or a placebo solution containing no active ingredient, was applied to the scalp and both thighs to maximise the surface area for absorption. Volunteers were admitted to the study unit on Day -1, dosed twice daily on Days 1-3, and once on Day 4. They were discharged on Day 6 and had a telephone follow-up on Day 14.
Pre- and post-dose 12-lead resting ECG recordings were collected during the study, generating robust cardiac data. Blood samples were also taken at specified time points to measure the amount of cortexolone in the bloodstream. The sensitivity of the assay to consistently detect small changes in QTc was assessed by measuring the effect of food as previously described³.
Fluctuations in the QTc interval were seen throughout the day, but these were not caused by drug administration. Although a small, non-significant shortening effect was seen at some time points, this was likely due to the known effect of cortexolone on hERG potassium channels. All 95% confidence intervals4 were negative, with point estimates around −5 milliseconds or below, confirming the sensitivity of the assay.
Concentrations of cortexolone in the bloodstream increased gradually on initial application of the solution and noticeably quicker on the second and third application. Blood results also demonstrated that cortexolone accumulates and metabolises in the bloodstream with multiple applications.
Nine volunteers who applied cortexolone solution reported adverse events, half of which were considered related to cortexolone. All events were graded as mild, except one which was graded as moderate. None of the volunteers who applied the placebo solution experienced any adverse events.
The daily dose of cortexolone applied in this study was significantly higher (4.5-fold) than the highest dose previously tested in clinical trials. Therefore, the results of this study apply to other formulations of cortexolone, i.e., standard 1% cream formula.
The risk of cardiac toxicity with cortexolone use is deemed to be low. However, our findings provide confirmatory evidence that although cortexolone can affect the duration of QTc, the amount of drug in the bloodstream is unlikely to reach a concentration high enough to induce any cardiac effect.
The study results demonstrated the ability to detect QTcF changes at the 5-millisecond threshold, which is of regulatory interest and supports using a meal to demonstrate assay sensitivity, in line with our previous research.
Furthermore, cortexolone has previously been shown to be generally well-tolerated in healthy male and female volunteers, with the most common AEs being of mild severity. Our findings provided further supporting evidence in this regard.
Read the full results in the paper published in Clinical Pharmacology in Drug Development.
Authored by Georg Ferber, PhD, Dilshat Djumanov, PhD, Ulrike Lorch, MD, FFPM, Edward Jackson, BSc, MSc, PhD, MBChB, Joao Almeida Melo, James Rickard, MPharm, and Jorg Taubel, MD, FFPM, FESC.
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