Pharmacokinetic/pharmacodynamic evaluation of hydrocortisone therapy in pediatric patients with congenital adrenal hyperplasia
Open accessAbstract
OBJECTIVES: Patients with congenital adrenal hyperplasia (CAH) require lifelong replacement therapy with glucocorticoids. Optimizing hydrocortisone therapy is challenging, since there are no established cortisol concentration targets other than the cortisol circadian rhythm profile. 17-hydroxyprogesterone (17-OHP) concentrations are elevated in these patients and commonly used to monitor therapy. This study aimed to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of cortisol using 17-OHP as a biomarker in pediatric patients with CAH and to assess different hydrocortisone dosing regimens. METHODS: Cortisol and 17-OHP concentrations from 30 CAH patients (7-17 years of age) receiving standard hydrocortisone replacement therapy (5-20 mg) twice (n = 17) or 3 times (n = 13) daily were used to develop a PK/PD model. Sequentially, simulated cortisol concentrations for clinically relevant 3- and 4-times daily dosing regimens were compared with cortisol and 17-OHP target ranges and to concentrations in healthy children. RESULTS: Cortisol concentration-time profiles were accurately described by a 2-compartment model with first-order absorption and expected high bioavailability (82.6%). A time-delayed model with cortisol-mediated inhibition of 17-OHP synthesis accurately described 17-OHP concentrations. The cortisol concentration inhibiting 50% of 17-OHP synthesis was 48.6 nmol/L. A 4-times-daily dosing better attained the target ranges and mimicked the cortisol concentrations throughout the 24-hour period than 3-times-daily. CONCLUSIONS: A PK/PD model following hydrocortisone administration has been established. An improved dosing regimen of 38% at 06:00, 22% at 12:00, 17% at 18:00, and 22% at 24:00 of the daily hydrocortisone dose was suggested. The 4-times-daily dosing regimen was superior, avoiding subtherapeutic cortisol concentrations and better resembling the circadian rhythm of cortisol.
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References 35 · Cited by 34
Research works printed but not linked: 2
- Ahmed M, Sarafoglou K, Al-Kofahi M, MT G-B, RC B. A model- based pharmacokinetic/pharmacodynamic analysis of hydrocor- tisone, 17-hydroxyprogesterone (17OHP), and androstenedione (D4A) in children with congenital adrenal hyperplasia (CAH). J Pharmacokinet Pharmacodyn. 2016;43:S89.
- Hindmarsh PC. The child with difficult to control Congenital Adrenal Hyperplasia: is there a place for continuous sub- cutaneous hydrocortisone therapy. Clin Endocrinol (Oxf). 2014;81(1):15-18.
- Authors
- Melin, J., Parra-Guillen, Z. P., Michelet, R., Truong, T., Huisinga, W., Hartung, N., Hindmarsh, P., & Kloft, C.
- Affiliations
- Freie Universität Berlin (DE)
- University of Potsdam (DE)
- University College London (GB)
- Corresponding author
- Melin, Johanna
- Kloft, Charlotte
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2020-03-03
- Volume
- 105
- Issue
- 4
- Pages
- e1729-e1740
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W3006629634
- Cited by
- 34
- References
- 35
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 3 · 2020: 3
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- publish.UP (University of Potsdam) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- congenital adrenal hyperplasia, cortisol, glucocorticoid replacement therapy, pharmacokinetics/pharmacodynamics, 17-hydroxyprogesterone, diurnal cortisol rhythm, dosing regimen optimization, pharmacokinetic-pharmacodynamic modeling, pediatric patients
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Anti-Inflammatory Agents, Biological Availability, Child, Circadian Rhythm, Female, Follow-Up Studies, Humans, Hydrocortisone, Male, Prognosis, Tissue Distribution, Biomarkers, 17-alpha-Hydroxyprogesterone, Hormone Replacement Therapy
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