Predicting Residual 21-Hydroxylase Enzymatic Activity in Pediatric and Adult Congenital Adrenal Hyperplasia Patients: Towards Individualized Therapy

Abstract

Congenital adrenal hyperplasia (CAH) is a genetic disorder characterized by impaired cortisol production and consequent elevated adrenocorticotropic hormone (ACTH): CAH patients often require lifelong hydrocortisone therapy. Disease severity reflects residual 21-hydroxylase enzyme activity, crucial for cortisol synthesis. Accurate assessment of residual enzymatic activity is key to developing individualized dosing. This study aimed to estimate enzymatic activity using a previously developed healthy adult ACTH-cortisol model and to evaluate the potential for individualized therapy. Leveraging ACTH (n = 62) and cortisol (n = 66) concentrations from 51 (20 pediatric, 31 adult) untreated CAH patients, and assuming maximal cortisol production (Emax) = 100% in healthy individuals, residual enzymatic activity was estimated as an Emax scaling factor. To assess proof-of-concept feasibility of individualized therapy, simulations of individual untreated 24-h ACTH and cortisol profiles were performed, and for one patient hydrocortisone dosing regimens (15–25 mg/day in 3 doses, q4h or q6h) were compared to simulated untreated and healthy profiles. The original model failed to capture elevated ACTH in severe CAH and was refined to predict observed data across all patients. Using the refined model, estimated enzymatic activity was higher than in vitro values for adults, while children under 13 years old showed 31.6% of adult enzymatic activity. Shortening dosing intervals had a greater impact on reducing the patient's ACTH overexposure than increasing the daily dose. This model-based approach captured in vivo endogenous cortisol production and enabled simulation-based evaluation of individualized therapy in adults. In children, further validation of the ACTH-cortisol dynamics model and enzymatic activity estimates is needed to evaluate individualized therapy.