Optimising prednisolone or prednisone replacement in adrenal insufficiency

Context: Patients with adrenal insufficiency (AI) have a higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with t wice- or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance through its convenience. Objectives: Prednisolone day curves can be used to accurately downtitrate patients to the minimum effective dose. This study aimed to review prednisol one day curves and determine therapeutic ranges at different time points after admi nistration. Methods: Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Spearman’s correlation coefficient was used to determine the relationship between 2-, 4-, and 6-h prednisolone levels compared to the previously validated standard 8-h prednisolone level (15–25 μg/L). Results: The median dose was 4 mg of prednisolone once daily. There was a strong correlation between the 4- and 8-h (R = 0.8829, P ≤ 0.0001) and 6- and 8-h prednisolone levels (R = 0.9530, P ≤ 0.0001). Target ranges for prednisolone were 37–62 μg/L at 4 h, 24–39 μg/L at 6 h, and 15–25 μg/L at 8 h. Prednisolone doses were successfully reduced in 21 individuals, and of these, 3 were reduced to 2 mg once daily. All patients were well upon follow-up. Conclusion: This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low-dose prednisolone of 2–4 mg is safe and effective in most pa tients with AI. Doses can be titrated with either 4-, 6-, or 8-h single time point drug levels.