Abstract

BackgroundGlucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7–14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose–response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.MethodsIn this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5–60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8.ResultsDaily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects.ConclusionsThis characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile.Trial registration numberNCT02767089 (retrospectively registered: 21 April 2016).

Highlights

  • Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent

  • Glucocorticoids (GCs) are commonly used to manage inflammatory and immunologically-mediated conditions [1,2,3], and continue to have a prominent place in the clinic despite having a profile of serious adverse effects that are dose- and time-dependent [4, 5]. Due to these known serious adverse effects, a GC such as prednisone is used at the lowest effective dose (5–7.5 mg daily) for chronic conditions such as rheumatoid arthritis (RA); the use of higher doses is limited to the shortest treatment duration required for management of acute conditions and disease exacerbations [6, 7]

  • Indianapolis, IN) was used initially for measurement of cortisol in serum, but the results indicated the possibility of assay interference from prednisone and its metabolite prednisolone

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Summary

Introduction

Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Glucocorticoids (GCs) are commonly used to manage inflammatory and immunologically-mediated conditions [1,2,3], and continue to have a prominent place in the clinic despite having a profile of serious adverse effects that are dose- and time-dependent [4, 5] Due to these known serious adverse effects, a GC such as prednisone is used at the lowest effective dose (5–7.5 mg daily) for chronic conditions such as rheumatoid arthritis (RA); the use of higher doses is limited to the shortest treatment duration required for management of acute conditions and disease exacerbations [6, 7]. Due to a plethora of effects on leukocytes and vascular endothelial cells, such as altered cell distribution patterns, immobilization, and apoptosis, GC therapy can result in dramatic changes in circulating white blood cell profiles that may contribute to an increased risk of GC-associated infection [12,13,14]

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