Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixant
Abstract 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‐pa...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-08-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12978 |
| _version_ | 1797742352810377216 |
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| author | Akshita Chawla Anna Largajolli Azher Hussain Huub Kleijn Sihem Ait‐Oudhia Judith Anton Hari Krishna Ananthula Jesse Nussbaum Carmen La Rosa Ferdous Gheyas |
| author_facet | Akshita Chawla Anna Largajolli Azher Hussain Huub Kleijn Sihem Ait‐Oudhia Judith Anton Hari Krishna Ananthula Jesse Nussbaum Carmen La Rosa Ferdous Gheyas |
| author_sort | Akshita Chawla |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T14:39:38Z |
| format | Article |
| id | doaj.art-f02f6d139f104ee19b3664f8304c3f9a |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-12T14:39:38Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-f02f6d139f104ee19b3664f8304c3f9a2023-08-16T15:38:05ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-08-011281107111810.1002/psp4.12978Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixantAkshita Chawla0Anna Largajolli1Azher Hussain2Huub Kleijn3Sihem Ait‐Oudhia4Judith Anton5Hari Krishna Ananthula6Jesse Nussbaum7Carmen La Rosa8Ferdous Gheyas9Merck & Co., Inc. Rahway New Jersey USACertara Strategic Consulting Princeton New Jersey USAMerck & Co., Inc. Rahway New Jersey USACertara Strategic Consulting Princeton New Jersey USAMerck & Co., Inc. Rahway New Jersey USAMerck & Co., Inc. Rahway New Jersey USAMerck & Co., Inc. Rahway New Jersey USAMerck & Co., Inc. Rahway New Jersey USAMerck & Co., Inc. Rahway New Jersey USAMerck & Co., Inc. Rahway New Jersey USAAbstract 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.https://doi.org/10.1002/psp4.12978 |
| spellingShingle | Akshita Chawla Anna Largajolli Azher Hussain Huub Kleijn Sihem Ait‐Oudhia Judith Anton Hari Krishna Ananthula Jesse Nussbaum Carmen La Rosa Ferdous Gheyas Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixant CPT: Pharmacometrics & Systems Pharmacology |
| title | Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixant |
| title_full | Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixant |
| title_fullStr | Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixant |
| title_full_unstemmed | Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixant |
| title_short | Population pharmacokinetic analysis of the P2X3‐receptor antagonist gefapixant |
| title_sort | population pharmacokinetic analysis of the p2x3 receptor antagonist gefapixant |
| url | https://doi.org/10.1002/psp4.12978 |
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