Population pharmacokinetic analysis of the P2X3-receptor antagonist gefapixant

CPT Pharmacometrics Syst Pharmacol. 2023 Aug;12(8):1107-1118. doi: 10.1002/psp4.12978. Epub 2023 Jun 15.


Gefapixant, a P2X3-receptor antagonist, demonstrated objective and subjective efficacy in individuals with refractory or unexplained chronic cough. We report a population pharmacokinetic (PopPK) analysis that characterizes gefapixant pharmacokinetics (PKs), quantifies between- and within-participant variability, and evaluates the impact of intrinsic and extrinsic factors on gefapixant exposure. The PopPK model was initially developed using PK data from six phase I studies. Stepwise covariate method was utilized to identify covariates impacting PK parameters; the model was re-estimated and covariate effects were re-assessed after integrating PK data from three phase II and III studies. Simulations were conducted to evaluate the magnitude of covariate effects on gefapixant exposure. Of 1677 participants included in this data set, 1618 had evaluable PK records. Age, body weight, and sex had statistically significant, but not clinically relevant, effects on exposure. Degree of renal impairment (RI) had statistically significant and clinically relevant effects on exposure; exposure was 17% to 89% higher in those with versus without RI. Simulation results indicated that gefapixant 45 mg administered once daily to patients with severe RI has similar exposure to gefapixant 45 mg administered twice daily to patients with normal renal function. There were no significant effects of proton pump inhibitors or food. Of evaluated intrinsic and extrinsic factors, only RI had a clinically relevant effect on gefapixant exposure. Patients with mild or moderate RI do not require dosage adjustments; however, for patients with severe RI who are not on dialysis, gefapixant 45 mg once daily is recommended.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cough* / chemically induced
  • Humans
  • Pyrimidines / adverse effects
  • Renal Dialysis
  • Renal Insufficiency*
  • Sulfonamides


  • Gefapixant
  • Sulfonamides
  • Pyrimidines