Summary: A 2025 report combined a healthy-volunteer pharmacokinetic study with a post hoc analysis of 63 patients with congenital adrenal hyperplasia (CAH). Relative cortisol exposure was 108% (90% CI 103%-113%), and switching to modified-release hydrocortisone improved morning androgen markers over four weeks; these are not long-term clinical outcomes.
PICO Summary
| Element | Detail |
|---|---|
| Population | Two distinct populations: 25 healthy men aged 18-45 randomised in a UK crossover study, 24 completing and 21 eligible for the primary AUC analysis; separately, 63 patients with classic 21-hydroxylase-deficient CAH taking immediate-release hydrocortisone alone at baseline, selected from a 122-patient phase 3 trial. |
| Intervention | Pharmacokinetics: single 20-mg modified-release hydrocortisone capsule dose during dexamethasone suppression, crossed over with immediate-release treatment. CAH subgroup: 32 patients switched to the same total daily hydrocortisone dose, approximately two thirds at bedtime and one third on awakening. This describes the research protocol, not instructions for individual dose changes. |
| Comparator | Pharmacokinetics: a single 20-mg immediate-release hydrocortisone dose in the other crossover period. CAH subgroup: 31 patients continued immediate-release hydrocortisone. Routine titration was withheld during the four-week analysis, except for safety-related changes. |
| Outcomes | Primary pharmacokinetic endpoint: cortisol AUC0-inf ratio 108% (90% CI 103%-113%), within the stated 80%-125% range; 21 participants contributed to the primary analysis. In the post hoc CAH subgroup at four weeks, median 09:00 17-hydroxyprogesterone change was -52.1 versus +7 nmol/L (P=0.0003), and median androstenedione change was -1.5 versus +0.1 nmol/L (P=0.0031). Geometric mean endpoint concentrations were 8.0 versus 28.7 nmol/L for 17-hydroxyprogesterone (P=0.0196) and 1.7 versus 2.8 nmol/L for androstenedione (not significant). Confidence intervals for these subgroup contrasts were not supplied. No severe or serious treatment-emergent events were reported in the pharmacokinetic study. No adrenal crises occurred in either CAH group over four weeks; sick-day stress-dosing episodes numbered nine versus eight. |
| Study Design | Original 2025 publication combining an open-label, randomised two-period pharmacokinetic crossover study (NCT03343327) with a post hoc four-week subgroup analysis of phase 3 trial NCT03062280. This is not a new independently randomised switching trial. Initiated and supported by Diurnal, now Neurocrine UK, with company employees and consultants among authors. |
Expert Commentary
I regard this report as a useful pharmacological and biochemical explanation of switching formulations, not a definitive trial of improved patient outcomes. Comparable total cortisol exposure in healthy volunteers supports the formulation comparison, while the CAH analysis suggests better morning androgen control after switching. These findings come from different populations and should not be merged into a single efficacy cohort. Can I use this with my patients? The evidence can inform a specialist discussion for patients with classic CAH already receiving immediate-release hydrocortisone, but it should not be converted into an unsupervised switching schedule. The central limitation is that the clinical findings are a short, post hoc subgroup analysis of an existing trial. They cannot establish effects on fertility, quality of life, metabolic complications or long-term adrenal crisis risk. No crises over four weeks is reassuring only within that narrow observation period, and stress dosing was still required. The distinction between changes in androstenedione and its nonsignificant endpoint concentration comparison also deserves care. Manufacturer support and author affiliations should remain visible when interpreting the practical conclusions. I would want prospective evaluation of switching strategies with patient-centred outcomes, standardised biochemical sampling and longer safety follow-up before presenting this regimen as an established improvement in overall care.
References
Ross RJM, Arlt W, de la Perriere AB, et al. Switching Patients With Congenital Adrenal Hyperplasia to Modified-Release Hydrocortisone Capsules: Relative Bioavailability and Disease Control. Clin Endocrinol (Oxf). 2025;103(3):290-293. doi:10.1111/cen.15275. PMID: 40377230.
