Endocrine Abstracts

Patients with adrenal insufficiency need adjustment of the hydrocortisone (HC) dose during an intercurrent illness. Current recommendation to double the daily HC dose at each occasion does not consider the non-linear dose proportionality in bioavailability i.e. doubling the dose gives less than 100% increase in exposure. We have developed an intercurrent illness dose regimen for a once daily dual release HC tablet using population pharmacokinetic (POPPK) modeling.

Methods: Cortisol serum concentration time profiles were obtained in 62 patients after administraton of oral once daily dual release HC tablets (20–60 mg) on 116 occasions, and in healthy volunteers (after betametasone suppression) after single 5 (n=14) and 20 mg (n=16) doses. All data was simultaneously modeled using a POPPK modeling approach in NONMEM. Simulations were made in order to investigate optimal intercurrent illness dosing regimens. The safety of the optimal regimen was thereafter studied in a prospective study in patients with Addison’s disease.

Results: Simulated data demonstrated that adding an additional dose at 8±2 hours after the morning dose resulted in slightly higher peak concentrations for the second dose and increased cortisol levels during the evening and early night time. Giving three daily doses with 8-hour intervals resulted in no dose accumulation on the day after, but with cortisol levels during the night. The dual release HC b.i.d. or t.i.d. intercurrent illness regimen gives less fluctuations and higher cortisol concentrations in the afternoon compared to immediate release. Prospective collection of data in 173 patient years demonstrated that changing the dosing interval of the dual release tablets from o.d. to b.i.d. (or t.i.d.) during undercurrent illness was safe.

Conclusion: The daily dual release HC dose given twice or thrice daily with 8±2 hours intervals during intercurrent illness increases the 24 h cortisol coverage and has been documented to be safe.

Declaration of interest: I fully declare a conflict of interest. Details below:

Funding: This work was supported, however funding details unavailable.