LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

Yan Jin, Claire Smith, Leijun Hu, David E Coutant, Kelly Whitehurst, Krista Phipps, Terry Ann McNearney, Xiao Yang, Bradley Ackermann, Thomas Pottanat, William Landschulz, Yan Jin, Claire Smith, Leijun Hu, David E Coutant, Kelly Whitehurst, Krista Phipps, Terry Ann McNearney, Xiao Yang, Bradley Ackermann, Thomas Pottanat, William Landschulz

Abstract

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070.

© 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Time course of LY3127760 (LY) plasma concentrations (arithmetic mean ± SD) following administration on days 1 and 28. Doses were 20 mg q.d. (a), 60 mg q.d. (b), 200 mg q.d. (c), and 300 mg b.i.d. (d). *For the 300 mg b.i.d. dose, subjects received only a single dose on day 1 and day 28. Conc, concentration ; QD, once daily; SD, standard deviation
Figure 2
Figure 2
Percent change from baseline (day ‐1) in ex vivo tumor necrosis factor alpha (TNF‐α) release on day 1 (a) and day 28 (b). Bars represent geometric LY3127760 (LS) means; error bars represent 90% confidence interval (CI). *P < 0.05 compared with placebo; **P < 0.05 compared with celecoxib BID, twice daily; CI, confidence interval; LY, LY3127760; QD, once daily.
Figure 3
Figure 3
Changes in 24‐h urinary sodium excretion (a), urinary potassium excretion (b), and creatinine clearance (c) in response to LY3127760 (LY) and celecoxib dosing on days 1 and 27. Bars represent geometric least squares means; error bars represent 90% confidence interval (CI). *P < 0.05 compared with placebo; **P < 0.05 compared with celecoxib BID, twice daily; CI, confidence interval; LY, LY3127760; QD, once daily.
Figure 4
Figure 4
Changes in 24‐h urinary excretion of prostaglandin E metabolite (PGEM) (a), prostacyclin metabolite (PGIM) (b), and thromboxane A2 metabolite (TXAM) (c) in response to LY3127760 (LY) and celecoxib dosing on days 1 and 27. Bars represent geometric least squares means; error bars represent 90% confidence interval (CI). *P < 0.05 compared with placebo; **P < 0.05 compared with celecoxib.
Figure 5
Figure 5
Changes in 24‐h serum thromboxane B2 (TXB2) in response to LY3127760 (LY) and celecoxib dosing on days 1 and 28. Bars represent geometric least square means; error bars represent 90% confidence interval (CI). *P

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