Modified-release hydrocortisone to provide circadian cortisol profiles

Abstract

Context: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm.

Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles.

Setting: The study was performed at a Clinical Research Facility.

Design and methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen.

Results: The key variables in the physiological cortisol profile included: peak 15.5 microg/dl (95% reference range 11.7-20.6), acrophase 0832 h (95% confidence interval 0759-0905), nadir less than 2 microg/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) microg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels.

Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.

Figure 1

Physiological cortisol circadian rhythm. The figure shows the geometrical mean (−) ± 2 sd values (−) of serum cortisol concentration calculated from 20 min sampling over a 24-h period in 33 healthy subjects. The fitted cosinor (−) is the average of harmonic regressions that were a fit for the individual subject data. Cortisol has a distinct circadian rhythm with a peak of 15.5 μg/dl (95% reference range 11.7–20.6) occurring at 0832 h and a nadir (time of trough cortisol level) less than 2.0 μg/dl (95% reference range 1.5–2.5) at 0018 h. The mean and 95% CI are shown for the mesor (midline estimating statistic of rhythm), acrophase (time of peak using a 24 h clock with midnight taken as origin), and nadir. mcg, μg.

Figure 2

Concentration-time profiles for MR-HC and IR-HC. Concentration-time profiles for different doses of MR-HC given at 2200 h compared with 10 mg IR-HC using geometrical means (±sem) of serum cortisol concentrations at 18 different time points over 24 h. Profiles of MR-HC show a prolonged T_max, T_lag, and a lower dose-adjusted C_max (data not shown) when compared with IR-HC, all typical of a formulation with delayed and sustained release characteristics. mcg, μg.

Figure 3

Simulation of physiological (Physio) cortisol rhythm using MR-HC. Phase 1 PK data were used to simulate giving MR-HC doses at different times and once or twice daily. PK modeling included comparison of MR-HC with the physiological cortisol rhythm over 12 and 24 h, and at different time intervals (trapezoidal segments), using AUCs. The graph shows modeled concentration-time profile (−) obtained when giving 20 mg (15 plus 5 mg) MR-HC at 2300 h and 10 mg MR-HC at 0700 h superimposed on the physiological cortisol rhythm [geometrical mean (−) ± 2 sd values (−) of serum cortisol concentration calculated from 20 min sampling over a 24-h period in 33 healthy subjects].mcg, μg.