Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

Abstract

Background and objective: There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers.

Methods: We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant.

Results: Peak plasma concentrations of eliapixant were reached 3-4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak-trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events.

Conclusions: Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough.

Clinical trial registration: Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017).

Fig. 1

Model-based predicted typical exposure for healthy volunteers, compared with the exposure observed with a single dose of 800 mg administered after a high-fat/high-calorie breakfast (black solid line), shown in relation to three levels of inhibitory concentration (IC). Day 0: maintenance dose twice daily (BID), day 1: loading dose three times daily (0, 6, 12 h), days 2–13: maintenance dose BID. Upper left (dose level 1): 10 mg as a loading and maintenance dose. Upper right (dose level 2): 50 mg as a loading and maintenance dose. Lower left (dose level 3): 200 mg as a loading and maintenance dose. Lower right (dose level 4): 750 mg as a loading and maintenance dose. Dashed horizontal lines indicate ICs for 20, 50, and 80% of receptors (IC₂₀, IC₅₀, IC₈₀; the latter is the expected threshold for efficacy)

Fig. 2

Subject disposition. ^aPremature termination of eliapixant (n =1). Raised liver function tests associated with Epstein–Barr virus infection, not considered related to the study drug. Resolved after drug discontinuation. ^bPremature termination of placebo (n =1). Withdrawal by subject (personal reasons)

Fig. 3

Geometric mean (standard deviation) plasma concentrations of eliapixant over a 0–24 h and b day 0–day 20 (semi-logarithmic scale). Upper horizontal line represents the concentration of eliapixant (141 μg L^–1) predicted from preclinical/in vitro data to reach 80% P2X3 receptor occupancy, the expected relevant threshold for efficacy (unpublished data, Bayer AG, Berlin, Germany). h hours, LLOQ lower limit of quantification (1 μg L^–1), RO₈₀ concentration required to achieve 80% P2X3 receptor occupancy

Fig. 4

Mean change (standard error of the mean [SEM]) from baseline in overall taste score from taste strips