Chronopharmacology of glucocorticoids

Abstract

Glucocorticoids influence a wide array of metabolic, anti-inflammatory, immunosuppressive, and cognitive signaling processes, playing an important role in homeostasis and preservation of normal organ function. Synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is the primary glucocorticoid in humans. Synthetic glucocorticoids are important pharmacological agents that augment the anti-inflammatory and immunosuppressive properties of endogenous cortisol and are widely used for the treatment of asthma, Crohn's disease, and rheumatoid arthritis, amongst other chronic conditions. The homeostatic activity of cortisol is disrupted by the administration of synthetic glucocorticoids and so there is interest in developing treatment options that minimize HPA axis disturbance while maintaining the pharmacological effects. Studies suggest that optimizing drug administration time can achieve this goal. The present review provides an overview of endogenous glucocorticoid activity and recent advances in treatment options that have further improved patient safety and efficacy with an emphasis on chronopharmacology.

Keywords: Chronopharmacokinetics; Chronopharmacology; Circadian rhythms; Cortisol; HPA axis disruption; Synthetic glucocorticoids.

Figure 1:

Therapeutic and adverse effects associated with glucocorticoid therapies. Glucocorticoid treatment is accompanied by several adverse effects across peripheral tissues and many biological processes. For safe and effective treatment, the therapeutic benefits of synthetic glucocorticoid administration must outweigh the risk of these adverse effects. Figure adapted from Liu et al. [6] and Buttgereit et al. [30].

Figure 2:

Systemic and tissue-level regulation of glucocorticoids. Glucocorticoid synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis, comprised of stimulatory and negative feedback signals which control the secretion of corticotrophin-releasing hormone (CRH) from the hypothalamus, adrenocorticotrophic hormone (ACTH) from the pituitary gland and finally cortisol from the adrenal glands. The 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme system is responsible for the activation and deactivation of cortisol, which in part is responsible for local regulation of cortisol. Cortisol induces its pleiotropic influences on peripheral tissues through glucocorticoid receptor-mediated actions, supporting the normal physiology and functioning of these organ systems. Figure adapted from Cruz-Tropete et al. [34, 51] and Oakley et al. [52].

Figure 3:

Concentration-time profiles for synthetic glucocorticoids and endogenous cortisol. The plasma concentration profiles after administration of a single dose at 8 AM are shown for a hydrocortisone injection, prednisolone tablet, methylprednisolone injection, and dexamethasone injection. The cortisol profiles for the baseline (placebo) and after treatment with prednisolone, methylprednisolone, or dexamethasone are given. Because endogenous cortisol and hydrocortisone are indistinguishable in the biochemical assay used for this study, the total cortisol level following dosing with hydrocortisone is shown. Figure drawn using data from D.E. Mager, S.X. Lin, R.A. Blum, C.D. Lates, W.J. Jusko, Dose equivalency evaluation of major corticosteroids: Pharmacokinetics and cell trafficking and cortisol dynamics, Journal of Clinical Pharmacology, 43 (2003) 1216–1227.

Figure 4:

Time-dependent differences in adrenal suppression following methylprednisolone infusions. The time-concentration profiles of 17-OHCS, a metabolite of cortisol excreted in urine, are shown following 4-hour methylprednisolone infusions for the following time windows: 00:00 to 04:00, 04:00 to 08:00, 08:00 to 16:00, and 16:00 to 20:00. Solid circles represent the control (no drug infusion) and open squares represent the drug-modified cortisol rhythm. Figure drawn using data from Angeli A. Circadian ACTH-adrenal rhythm in man. Chronobiologia. 1974 Sep;1 Suppl 1:253–68. Reprinted from: Haus E, Sackett-Lundeen L, Smoilensky MH. Rheumatoid arthritis: circadian rhythms in disease activity, signs and symptoms, and rationale for chronotherapy with corticosteroids and other medications. Bull Hosp Jt Dis. 2012;70(Suppl 1):S3–10. With permission.

Figure 5:

Plasma concentration profiles for conventional prednisone and modified-release prednisone tablets. The time-concentration profiles of a conventional immediate release prednisone tablet (administered at 2 AM) and modified-release prednisone tablets (administered at 8 PM) after a light meal at 5:30 PM or dinner at 7:30 PM are provided. Figure drawn using data from S.P. Beltrametti, A. Ianniello, C. Ricci, Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review, Ther Clin Risk Manag, 12 (2016) 1763–1776.

Figure 6:

Concentration-time profiles for cortisol replacement studies. The left panel shows cortisol profiles following a circadian infusion of hydrocortisone (HC) via a pump and administration of a conventional hydrocortisone tablet in patients with Addison’s disease and congenital adrenal hyperplasia. The right panel shows the cortisol profiles following administration of a modified release hydrocortisone tablet at 10PM in healthy individuals with suppression of endogenous cortisol by dexamethasone. Figure drawn using data from M. Debono, R.J. Ross, J. Newell-Price, Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy, Eur J Endocrinol, 160 (2009) 719–729.

Figure 7:

Modeling chronopharmacological dosing of synthetic glucocorticoids using a physiologically-based HPA axis model. The concentration-time profiles for a bolus injection, fast-releasing oral dose, and a slow-releasing oral dose are given in Panel A. The nominal cortisol profile predicted by the model is given in Panel B. The relative amplitude change (%difference in amplitude before and after once-daily dosing of synthetic glucocorticoids) are given for several dosing times in Panel C, where a positive value indicates induction of the cortisol rhythm and a negative value indicates suppression of the cortisol rhythm. The difference in phase of the cortisol rhythm before and after treatment with synthetic glucocorticoids for several dosing times are given in Panel D, where a positive value indicates delayed timing of the cortisol peak and a negative value indicates an advance in the timing of the cortisol peak. Figure drawn using data from R.T. Rao, M.L. Scherholz, I.P. Androulakis, Modeling the influence of chronopharmacological administration of synthetic glucocorticoids on the hypothalamic-pituitary-adrenal axis, Chronobiol Int, (2018) 1–18.

Figure 8:

Circadian rhythmicity of physiological functions in humans. The peak time or acrophase of several biological processes in humans are shown relative to the sleep-wake cycle, indicating distribution of biological processes across the 24-hour day under normal physiology. Figure adapted from Smolensky et al. [41].