Abstract

Background: We developed a modified-release hydrocortisone, Chronocort®, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption and it is important to assess their impact when replicating a physiological rhythm. Subjects and Methods: In vitro dissolution to study impact of alcohol and pH on Chronocort®. A Phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort® and to compare bioavailability to immediate-release hydrocortisone. Results: In vitro dissolution of Chronocort® was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20 % v/v. Food delayed and reduced the rate of absorption of Chronocort® as reflected by a longer Tmax (fed vs fasted: 6.75 hrs vs 4.5 hrs, p=0005) and lower Cmax (549.49 vs 708.46, nmol/L, ratio 77% with CI 71 – 85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0 t for fed/fasted was 108.33% (102.30 – 114.72%). Cortisol exposure was higher for Chronocort® compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58 – 126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0 125.0 %: Geo LSmean ratio (CI) for AUC0 t 112.73% (105.33 – 120.65%). Conclusions: Gastric pH ≤ 6.0 and alcohol do not effect hydrocortisone release from Chronocort®. Food delays Chronocort® absorption but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort® and immediate-release hydrocortisone.

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