Johanna Melin (1)(2), Peter Hindmarsh (3), Wilhelm Huisinga (4), Charlotte Kloft (1).
(1) Department of Clinical Pharmacy and Biochemistry, Freie Universitaet Berlin, Germany, (2) Graduate Research Training Program PharMetrX, (3) Department of Endocrinology, Great Ormond Street Hospital for Children, London, UK, (4) Institute of Mathematics, Universität Potsdam, Germany
Objectives: Patients with congenital adrenal hyperplasia (CAH) have an impaired synthesis of cortisol, leading to accumulation of cortisol precursors and elevated concentrations of androgens. Substitution therapy with glucocorticoids, especially in growing children, is important but challenging to optimise: Too high exposure to glucocorticoids may increase the risk of reducing final-height and development of Cushing’s syndrome, whereas too low exposure may increase the risk for Addisonian crisis and disease progression [1]. Dosing decisions are currently based on body weight or body surface area (BSA), and clinical signs of adrenal suppression. The objective of this study was to gain prior knowledge for an upcoming PK study in a new paediatric population, by characterising the pharmacokinetics of hydrocortisone (i.e., synthetic cortisol) in paediatric patients with CAH.
Methods: For model development, patients included in the study were 7-18 years old and diagnosed with CAH. Cortisol concentrations over 6 h were available after single intravenous (i.v.) administration of hydrocortisone succinate and cortisol concentrations over 24 hours after twice or thrice daily oral administration of hydrocortisone [2][3]. The i.v. dose was individualised based on BSA (dose range: 14.2 – 30.2 mg), and regular oral therapeutic regimens were administered twice or thrice daily (dose range: 2.5 – 20 mg). Population pharmacokinetic analysis was performed using NONMEM 7.3. Precision of parameter estimates was assessed by performing bootstraps.
Results: Concentrations from 16 patients after i.v. and from 30 patients after oral administration were used for model development. A one compartment model with first-order absorption and elimination successfully described the data under the different studied dosing regimens. The estimated parameters were in agreement with literature data [1][3][4], except for the bioavailability, which was lower (77.6 %). Interindividual variability was implemented in absorption rate constant, clearance, volume of distribution and bioavailability.
Conclusions: A population pharmacokinetic analysis for hydrocortisone in paediatric patients with congenital adrenal hyperplasia has successfully been developed. The model is intended to be used for establishing an optimal design for a study in patients younger than six years, and for optimising the hydrocortisone therapy in this patient group.
References:
[1] Charmandari E, Johnston a, Brook CG, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Endocrinol. (2001) 169(1):65–70.
[2] Charmandari E, Matthews DR, Johnston A, Brook CG, Hindmarsh PC. Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory? J. Clin. Endocrinol. Metab. (2001) 86(10):4679–85.
[3] Derendorf H, Mollmann H, Barth J, Mollmann C, Tunn S, Krieg M. Pharmacokinetics and oral bioavailability of hydrocortisone. J Clin Pharm. 1991;31(5):473–6.
[4] Simon N, Castinetti F, Ouliac F, Lesavre N, Brue T, Oliver C. Pharmacokinetic evidence for suboptimal treatment of adrenal insufficiency with currently available hydrocortisone tablets. Clin. Pharmacokinet. (2010) 49(7):455–63.
Reference: PAGE 23 (2014) Abstr 3106 [www.page-meeting.org/?abstract=3106]
Poster: Drug/Disease modeling - Paediatrics