Background: Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and\nimmunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse\neffects that are both dose and time dependent. Short-term treatment (7ââ?¬â??14 days) with oral prednisone is used for\nmany acute inflammatory and allergic conditions. This study was conducted to characterize the safety and\npharmacodynamic (PD) doseââ?¬â??response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.\nMethods: In this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects\nreceived placebo or a prednisone dose from 2.5ââ?¬â??60 mg daily over 7 days in each of three treatment periods. White\nblood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP)\nwere 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\ndosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen\n(uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing\non days 0, 1, 4 and 8.\nResults: Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin,\nplasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while\nblood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase\nwas observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and\nnervous system disorders, mainly headache, were the most frequently reported adverse effects.\nConclusions: This characterization provides important and relevant information on safety and PD responses of\nshort-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for\nearly clinical development of dissociated agents targeting a differentiated PD profile.
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