Abstract
Background and Objective
Adrenal insufficiency is caused by primary adrenal failure or by impairment of the corticotropic axis. In both situations, cortisol secretion is deficient, and hydrocortisone is a logical replacement therapy. However, no consensus guideline for dosing has been published, and clinicians adapt the dose empirically after only a clinical evaluation. Under this regimen, some patients receiving an inappropriately high dose of cortisol feel comfortable and also have an increased risk of adverse effects. We performed a pharmacokinetic study of cortisol in patients with adrenal insufficiency to evaluate plasma concentrations when the dosing was based on clinical examination and to develop a model allowing optimization of drug dosing.
Study Design
This was a prospective, open-label study in two endocrinology departments and a clinical investigation centre (Assistance Publique Hôpitaux de Marseille, Marseille, France).
Methods
Fifty patients with primary (n = 20) or secondary (n = 30) adrenal insufficiency were recruited. All patients were given their usual hydrocortisone replacement regimen. Blood samples for cortisol measurements were drawn at 0600, 0800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 and 0000 h. The observed values were compared with the known physiological range throughout the day (0800, 1600 and 0000 h). A population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling software (NONMEM®). The final pharmacokinetic model was then used to simulate several hydrocortisone dosing scenarios.
Results
Thirteen different treatment regimens for 50 patients were observed. The cortisol plasma concentrations were compared with the physiological range and showed that 79%, 55% and 45% of patients were over- or under-treated at 0800, 1600 and 2400 h, respectively. The cortisol concentrations showed wide variability and were best described using a one-compartment model with zero-order input and first-order elimination. The pharmacokinetic parameters (intersubject variability) were the following: duration of absorption 0.54 hour, volume of distribution 38.7 L (39.7%) and clearance 12.1 L/h (23.2%). The proportional residual error was 32.3%. This final model was then used to simulate 18 different dosing regimens. The regimen with the highest proportion of simulated patients within the physiological targets was 10 + 5 + 5 mg at 0730, 1200 and 1630 h, respectively. However, even with this regimen, about 54%, 44% and 32% of patients would remain over- or under-treated at 0800, 1600 and 2400 h, respectively.
Conclusions
Most patients with adrenal insufficiency are imperfectly treated with hydrocortisone relative to their plasma cortisol concentrations. Using simulation, a standard dosing regimen is suggested, which increases the proportion of patients within the physiological target concentrations. However, an individualized dose adjustment would be more accurate.
Similar content being viewed by others
References
Besser GM, Jeffcoate WJ. Endocrine and metabolic diseases: adrenal diseases. Br Med J 1976; 1: 448–51
Orth DN, Kovacs WJ, Wilson IJD, et al. Williams textbook of endocrinology. 9th ed. Philadelphia: WB Saunders Co., 1998: 517–5
Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol (Oxf) 2005; 63: 483–92
LovasK, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison’s disease. Clin Endocrinol (Oxf) 2002; 56: 581–8
Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, et al. Premature mortality in patients with Addisonś disease: a population-based study. J Clin Endocrinol Metab 2006; 91: 4849–53
Wichers M, Springer W, Bidlingmaier F, et al. The influence of hydrocortisone substitutiononthe qualityof life and parameters of bone metabolism in patients with secondary hypocortisolism. Clin Endocrinol (Oxf) 1999; 50: 759–5
Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336: 285–8
Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 2001; 357: 425–31
Blum WF, Shavrikova EP, Edwards DJ, et al. Decreased quality of life in adult patients with growth hormone deficiency compared with general populations using the new, validated, self-weighted questionnaire, Questions on Life Satisfaction Hypopituitarism Module. J Clin Endocrinol Metab 2003; 88: 4158–67
Filipsson H, Monson JP, Koltowska-Haggstrom M, et al. The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab 2006; 91: 3954–61
Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf) 1997; 46: 263–8
Mah PM, Jenkins RC, Rostami-Hodjegan A, et al. Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2004; 61: 367–75
Weitzman ED, Fukushima D, Nogeire C, et al. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab 1971; 33: 14–22
Beal S, Sheiner L, Boeckmann AJ, editors. NONMEM user’s guide. Ellicott City (MD): Icon Development Solutions, 1989–2006
Boeckmann A, Sheiner L, Beal S, editors. NONMEN user’s guide, part V. Ellicott City (MD): Icon Development Solutions, 1992
Karlsson MO, Jonsson EN, Wiltse CG, et al. Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients. J Pharmacokinet Biopharm 1998; 26: 207–46
Brendel K, Comets E, Laffont C, et al. Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 2006; 23: 2036–49
Arlt W, Rosenthal C, Hahner S, et al. Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs timed serum cortisol measurements. Clin Endocrinol (Oxf) 2006; 64: 384–9
Reynolds RM, Stewart PM, Seckl JR, et al. Assessing the HPA axis in patients with pituitary disease: a UK survey. Clin Endocrinol (Oxf) 2006; 64: 82–5
Merza Z, Rostami-Hodjegan A, Memmott A, et al. Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2006; 65: 45–50
Lovas K, Husebye ES. Continuous subcutaneous hydrocortisone infusion in Addison’s disease. Eur J Endocrinol 2007; 157: 109–12
Riedel M, Wiese A, Schurmeyer TH, et al. Quality of life in patients with Addison’s disease: effects of different cortisol replacement modes. Exp Clin Endocrinol 1993; 101: 106–11
Al-Shoumer KA, Ali K, Anyaoku V, et al. Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism. Clin Endocrinol (Oxf) 1996; 45: 171–8
Al-Shoumer KA, Beshyah SA, Niththyananthan R, et al. Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults. Clin Endocrinol (Oxf) 1995; 42: 85–90
Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004; 141: 764–70
Dekkers OM, Biermasz NR, Pereira AM, et al. Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2007; 92: 976–81
Charmandari E, Johnston A, Brook CG, et al. Bioavailability of oral hydro-cortisone in patients with congenital adrenal hyperplasia due to 21-hydro-xylase deficiency. J Endocrinol 2001; 169: 65–70
Newell-Price J, Whiteman M, Rostami-Hodjegan A, et al. Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexa-methasone-suppressed normal volunteers. Clin Endocrinol (Oxf) 2008; 68: 130–5
Debono M, Ghobadi C, Rostami-Hodjegan A, et al. Modified-release hydro-cortisonetoprovide circadian cortisol profiles. JClin Endocrinol Metab 2009; 94: 1548–54
Johannsson G, Filipsson H, Bergthorsdottir R, et al. Long-acting hydro-cortisone for glucocorticoid replacement therapy. Horm Res 2007; 68Suppl. 5: 182–8
Petrides JS, Gold PW, Mueller GP, et al. Marked differences in functioning of the hypothalamic-pituitary-adrenal axis between groups of men. J Appl Physiol 1997; 82: 1979–88
Huizenga NA, Koper JW, de Lange P, et al. Interperson variability but in-traperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin Endocrinol Metab 1998; 83: 47–54
Acknowledgements
Nicolas Simon and Frederic Castinetti contributed equally to this work.
The authors thank Michel Grino for his suggestions in the preparation of the manuscript, and Valerie Griset, Sylvie Bourrely and Gabrielle Belpassi for their help in the investigations.
This work was supported by a grant from Assistance Publique Hôpitaux de Marseille. The authors have no conflicts of interest that are directly relevant to the content of this study.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Simon, N., Castinetti, F., Ouliac, F. et al. Pharmacokinetic Evidence for Suboptimal Treatment of Adrenal Insufficiency with Currently Available Hydrocortisone Tablets. Clin Pharmacokinet 49, 455–463 (2010). https://doi.org/10.2165/11531290-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11531290-000000000-00000