Optimising prednisolone or prednisone replacement in adrenal insufficiency

Area of Science:

• Endocrinology
• Pharmacokinetics
• Clinical Pharmacology

Background:

• Adrenal insufficiency (AI) is associated with increased mortality, potentially due to inappropriate glucocorticoid exposure.
• Standard hydrocortisone replacement therapy requires multiple daily doses, complicating adherence and mimicking the natural cortisol rhythm.
• Once-daily prednisolone presents a convenient alternative for AI management, potentially improving patient compliance.

Purpose of the Study:

• To review prednisolone day curves in patients with AI.
• To determine therapeutic concentration ranges for prednisolone at various time points post-administration.
• To establish optimal dosing strategies for prednisolone replacement therapy.

Main Methods:

• Analysis of 108 prednisolone day curves from 76 patients receiving prednisolone replacement between August 2013 and May 2021.
• Quantification of prednisolone concentrations using ultra-high-performance liquid chromatography-tandem mass spectrometry.
• Correlation analysis of 2-, 4-, and 6-hour prednisolone levels against the validated 8-hour level using Spearman's correlation.

Main Results:

• A strong correlation was observed between 4-hour and 8-hour levels (R=0.8829) and 6-hour and 8-hour levels (R=0.9530).
• Established therapeutic ranges: 37-62 μg/L at 4 hours, 24-39 μg/L at 6 hours, and 15-25 μg/L at 8 hours.
• Prednisolone doses were successfully reduced in 21 patients, with 3 achieving a 2 mg once-daily dose, all remaining well on follow-up.

Conclusions:

• This study represents the largest evaluation of oral prednisolone pharmacokinetics in humans.
• Low-dose prednisolone (2-4 mg once daily) is safe and effective for managing AI in most patients.
• Prednisolone doses can be reliably titrated using single time point measurements at 4, 6, or 8 hours post-administration.