title: Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study.
abstract: 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. 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.
  
  
  
  In 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.
  
  
  
  Daily 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.
  
  
  
  This 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.
  
  
  
  NCT02767089 (retrospectively registered: 21 April 2016).
authors.affiliation: Pfizer Inc, Eastern Point Rd, Groton, CT, 06340, USA.
authors.forename: Dona L
authors.initials: DL
authors.lastname: Fleishaker
authors.affiliation: Pfizer Inc, Eastern Point Rd, Groton, CT, 06340, USA. arnab.mukherjee@pfizer.com.
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Innovative Analytics, 161 East Michigan Ave, Kalamazoo, MI, 49007, USA.
authors.forename: Fredrick S
authors.initials: FS
authors.lastname: Whaley
authors.affiliation: Jasper Clinic Inc, 526 Jasper Street, Kalamazoo, MI, USA.
authors.forename: Shanthini
authors.initials: S
authors.lastname: Daniel
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL, 60062, USA.
authors.forename: Bernhardt G
authors.initials: BG
authors.lastname: Zeiher
mesh_terms: D000284:Administration, Oral; D000328:Adult; D054316:Biomarkers, Pharmacological / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011241:Prednisone / Q000494:pharmacology*; D011347:Procollagen / Q000097:blood; D011965:Receptors, Glucocorticoid / Q000819:agonists; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; D005938:Glucocorticoids; D010446:Peptide Fragments; D011347:Procollagen; D011965:Receptors, Glucocorticoid; C047202:procollagen Type I N-terminal peptide; D015675:Osteocalcin; D011241:Prednisone; D006854:Hydrocortisone
keywords: Biomarker; Dose–response; Glucocorticoid; Healthy-subject; Pharmacodynamic; Prednisone; Safety