Johanna Melin (1)(2), Zinnia P Parra-Guillen (1), Niklas Hartung (1), Wilhelm Huisinga (3), Richard J Ross (4), Martin J Whitaker (5), Charlotte Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Insitute of Pharmacy, Freie Universitaet Berlin, Germany (2) and Graduate Research Training Program PharMetrX (3) Institute of Mathematics, Universitaet Potsdam, Germany (4) The University of Sheffield, UK (5) Diurnal Limited, Cardiff, UK
Objectives: Therapy optimisation of hydrocortisone (HC), synthetic cortisol, is challenging due to its nonlinear pharmacokinetics (PK) caused by several factors: i) cortisol is mainly bound with high affinity to corticosteroid binding globulin (CBG), and to a lesser extent to albumin and erythrocytes [1, 2, 3]. ii) The oral bioavailability of HC is dose-dependent, probably due to an increased first-pass metabolism or saturable absorption [2]. HC is equivalent to endogenous cortisol, and cannot be separated. The objective of this analysis was to characterise the PK of HC after administration of Infacort® (oral HC granules with taste masking) to healthy volunteers for future extrapolation.
Methods: Volunteers were suppressed with dexamethasone prior to receiving single doses of either 0.5, 2, 5 and 10 mg Infacort (n=16, study 1 [4]) or 20 mg Infacort and 20 mg HC iv (n=16, study 2) Total plasma concentrations were sampled up to 12 h post dose (rich sampling) and unbound concentrations (only study 2, sparse sampling) were analysed using ultrafiltration. A plasma protein binding model was established using unbound and total concentrations, and validated to previously published data [3]. The binding model was integrated into the disposition model, which was established in NONMEM 7.3 based on total concentrations. Predictive performance and parameter precision were assessed by visual predictive checks and bootstraping, respectively.
Results: A two compartment disposition model with a constant cortisol baseline (15 nmol/L, B1 method [5]), and considering both nonlinear and linear binding for HC described the data most accurately. Maximum binding capacity (Bmax) was 500 nmol/L, and the equilibrium dissociation constant (Kd) was 12 nmol/L. The binding model successfully predicted the published data in [3]. The saturable absorption indicated a nonlinear process for the three highest doses. Estimating a dose-dependent bioavailability improved model performance, and resulted in a reduction in bioavailability of approximately 40% for the 20 mg dose.
Conclusions: A semi-mechanistic population pharmacokinetic model for HC in healthy volunteers has been established. The model will be used further to predict exposure in paediatric patients and evaluated in further clinical trial results.
Acknowledgment: The work is being carried out under a Cooperation Agreement between Freie Universitaet and Diurnal funded by the European Commission FP7 Grant (No. 281654 TAIN).
References:
[1] RD Toothaker, PG Welling. Effect of dose size on the pharmacokinetics of intreavenous hydrocortisone during endogenous hydrocortisone suppression. J Pharmacokinet Biopharm 10: 147-156 (1982)
[2] RD Toothaker, WA Craig. Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension. J Pharm Sci 71: 1182-1185 (1982)
[3] EGWM Lentjes, FHTPM Romijn. Temperature-dependent cortisol distribution among the blood compartments in man. J Clin Endocrinol Metab 84: 682-687 (1999)
[4] M Whitaker, S Spielmann. Development and testing in healthy adults of oral hydrocortisone granules with taste masking for the treatment of neonates and infants with adrenal insufficiency. J Clin Endocrinol Metab 100: 1681-1688 (2015)
[5] C Dansirikul, H Silber. Approaches to handle pharmacodynamics baseline responses. J PKPD 35:269-83 (2008)
Reference: PAGE 25 (2016) Abstr 5764 [www.page-meeting.org/?abstract=5764]
Poster: Drug/Disease modeling - Endocrine