Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study

Dona L Fleishaker, Arnab Mukherjee, Fredrick S Whaley, Shanthini Daniel, Bernhardt G Zeiher, Dona L Fleishaker, Arnab Mukherjee, Fredrick S Whaley, Shanthini Daniel, Bernhardt G Zeiher

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration number: NCT02767089 (retrospectively registered: 21 April 2016).

Keywords: Biomarker; Dose–response; Glucocorticoid; Healthy-subject; Pharmacodynamic; Prednisone; Safety.

Figures

Fig. 1
Fig. 1
Mean serum cortisol concentrations up to 24 h following the first daily dose of prednisone. Pretreatment cortisol concentrations over 24 h were measured in all subjects the day prior to the first day of dosing in Period 1
Fig. 2
Fig. 2
Mean change from baseline (difference from placebo) in white blood cell counts. Eosinophil, neutrophil, and lymphocyte counts for Day 1 by hour (a, c, e) and for Days 1 through 8 (b, d, f) for each daily prednisone dose. *P ≤ 0.05 and **P ≤ 0.01 versus placebo
Fig. 3
Fig. 3
Mean change from baseline (difference from placebo) in biomarkers of bone metabolism. Change in osteocalcin (OC), procollagen type 1 N-propeptide (P1NP), and urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) for each daily dose of prednisone. a OC: Day 1 by hour; (b) OC: Days 1–8; (c) P1NP: Days 1–8; (d) uNTX: Days 1–8. *P ≤ 0.05 and **P ≤ 0.01 versus placebo

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