Douglas E James, Jason Bailey, Jan-Stefan van der Walt, Julia Winkler, Rik Schoemaker
{"title":"非匹奈巴特（LY3016859）和表调节素在慢性疼痛患者中的群体药代动力学和药效学。","authors":"Douglas E James, Jason Bailey, Jan-Stefan van der Walt, Julia Winkler, Rik Schoemaker","doi":"10.1007/s40262-025-01506-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed.</p><p><strong>Methods: </strong>Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks).</p><p><strong>Results: </strong>The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%.</p><p><strong>Conclusions: </strong>The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V<sub>c</sub>) than male sex, and DPNP was associated with lower V<sub>c</sub> than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC<sub>50</sub>).</p><p><strong>Trail registry: </strong>ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"757-767"},"PeriodicalIF":4.6000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064609/pdf/","citationCount":"0","resultStr":"{\"title\":\"Population Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain.\",\"authors\":\"Douglas E James, Jason Bailey, Jan-Stefan van der Walt, Julia Winkler, Rik Schoemaker\",\"doi\":\"10.1007/s40262-025-01506-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed.</p><p><strong>Methods: </strong>Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks).</p><p><strong>Results: </strong>The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%.</p><p><strong>Conclusions: </strong>The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V<sub>c</sub>) than male sex, and DPNP was associated with lower V<sub>c</sub> than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC<sub>50</sub>).</p><p><strong>Trail registry: </strong>ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.</p>\",\"PeriodicalId\":10405,\"journal\":{\"name\":\"Clinical Pharmacokinetics\",\"volume\":\"64 5\",\"pages\":\"757-767\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064609/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40262-025-01506-3\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/23 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40262-025-01506-3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/23 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Population Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain.
Background and objective: Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed.
Methods: Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks).
Results: The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%.
Conclusions: The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (Vc) than male sex, and DPNP was associated with lower Vc than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC50).
Trail registry: ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.
期刊介绍：
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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