Jessica Wojciechowski, Puneet Gaitonde, Jim H Hughes, Patanjali Ravva
{"title":"B型血友病患者接受非达那科基因治疗后因子IX活性的群体模型。","authors":"Jessica Wojciechowski, Puneet Gaitonde, Jim H Hughes, Patanjali Ravva","doi":"10.1007/s40262-025-01535-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>Fidanacogene elaparvovec (BEQVEZ™), an adeno-associated virus-based gene therapy approved for the treatment of hemophilia B, enables endogenous production of factor IX (FIX), preventing bleeding and reducing the need for FIX replacement. Nonlinear mixed-effects models are routinely used for population pharmacokinetic analyses of FIX replacement therapies but have not previously been applied to FIX activity observations from gene therapy trials. A nonlinear mixed-effects modeling approach was used to characterize FIX activity following fidanacogene elaparvovec and/or FIX replacement, identify covariates affecting FIX activity, and estimate the longer-term durability of FIX activity after a single dose of fidanacogene elaparvovec.</p><p><strong>Methods: </strong>Population modeling using NONMEM<sup>®</sup> was performed with FIX activity data pooled from 11 clinical trials in participants with hemophilia B (three fidanacogene elaparvovec studies [n = 63]; eight nonacog alfa studies [n = 274]). FIX activity was assessed by one-stage clotting assays.</p><p><strong>Results: </strong>FIX activity was described by a compartmental model for gene and protein expression and a three-compartment model for FIX disposition. Covariates included age and body weight on gene-therapy-related parameters. Following fidanacogene elaparvovec administration, model-predicted FIX activity reached a median (90% prediction interval) peak of 13.5 (3.12-41.3) IU/dL and remained within 50% of the peak for a median of 8.67 (0.411-15.0) years. At 15 years post-infusion, median predicted FIX activity was 4.11 (1.15-17.6) IU/dL.</p><p><strong>Conclusions: </strong>Model-based estimates showed that a single dose of fidanacogene elaparvovec elicited long-lasting elevations in FIX activity, suggesting most individuals would not require prophylactic FIX replacement for at least 15 years post-infusion.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT00364182, NCT01335061, NCT00037557, NCT00093171, NCT00093210, NCT03861273, NCT03307980, NCT02484092.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1531-1548"},"PeriodicalIF":4.0000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479722/pdf/","citationCount":"0","resultStr":"{\"title\":\"Population Modeling of Factor IX Activity Following Administration of Fidanacogene Elaparvovec Gene Therapy in Participants with Hemophilia B.\",\"authors\":\"Jessica Wojciechowski, Puneet Gaitonde, Jim H Hughes, Patanjali Ravva\",\"doi\":\"10.1007/s40262-025-01535-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>Fidanacogene elaparvovec (BEQVEZ™), an adeno-associated virus-based gene therapy approved for the treatment of hemophilia B, enables endogenous production of factor IX (FIX), preventing bleeding and reducing the need for FIX replacement. Nonlinear mixed-effects models are routinely used for population pharmacokinetic analyses of FIX replacement therapies but have not previously been applied to FIX activity observations from gene therapy trials. A nonlinear mixed-effects modeling approach was used to characterize FIX activity following fidanacogene elaparvovec and/or FIX replacement, identify covariates affecting FIX activity, and estimate the longer-term durability of FIX activity after a single dose of fidanacogene elaparvovec.</p><p><strong>Methods: </strong>Population modeling using NONMEM<sup>®</sup> was performed with FIX activity data pooled from 11 clinical trials in participants with hemophilia B (three fidanacogene elaparvovec studies [n = 63]; eight nonacog alfa studies [n = 274]). FIX activity was assessed by one-stage clotting assays.</p><p><strong>Results: </strong>FIX activity was described by a compartmental model for gene and protein expression and a three-compartment model for FIX disposition. Covariates included age and body weight on gene-therapy-related parameters. Following fidanacogene elaparvovec administration, model-predicted FIX activity reached a median (90% prediction interval) peak of 13.5 (3.12-41.3) IU/dL and remained within 50% of the peak for a median of 8.67 (0.411-15.0) years. At 15 years post-infusion, median predicted FIX activity was 4.11 (1.15-17.6) IU/dL.</p><p><strong>Conclusions: </strong>Model-based estimates showed that a single dose of fidanacogene elaparvovec elicited long-lasting elevations in FIX activity, suggesting most individuals would not require prophylactic FIX replacement for at least 15 years post-infusion.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT00364182, NCT01335061, NCT00037557, NCT00093171, NCT00093210, NCT03861273, NCT03307980, NCT02484092.</p>\",\"PeriodicalId\":10405,\"journal\":{\"name\":\"Clinical Pharmacokinetics\",\"volume\":\" \",\"pages\":\"1531-1548\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479722/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40262-025-01535-y\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/1 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/s40262-025-01535-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/1 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Population Modeling of Factor IX Activity Following Administration of Fidanacogene Elaparvovec Gene Therapy in Participants with Hemophilia B.
Background and objective: Fidanacogene elaparvovec (BEQVEZ™), an adeno-associated virus-based gene therapy approved for the treatment of hemophilia B, enables endogenous production of factor IX (FIX), preventing bleeding and reducing the need for FIX replacement. Nonlinear mixed-effects models are routinely used for population pharmacokinetic analyses of FIX replacement therapies but have not previously been applied to FIX activity observations from gene therapy trials. A nonlinear mixed-effects modeling approach was used to characterize FIX activity following fidanacogene elaparvovec and/or FIX replacement, identify covariates affecting FIX activity, and estimate the longer-term durability of FIX activity after a single dose of fidanacogene elaparvovec.
Methods: Population modeling using NONMEM® was performed with FIX activity data pooled from 11 clinical trials in participants with hemophilia B (three fidanacogene elaparvovec studies [n = 63]; eight nonacog alfa studies [n = 274]). FIX activity was assessed by one-stage clotting assays.
Results: FIX activity was described by a compartmental model for gene and protein expression and a three-compartment model for FIX disposition. Covariates included age and body weight on gene-therapy-related parameters. Following fidanacogene elaparvovec administration, model-predicted FIX activity reached a median (90% prediction interval) peak of 13.5 (3.12-41.3) IU/dL and remained within 50% of the peak for a median of 8.67 (0.411-15.0) years. At 15 years post-infusion, median predicted FIX activity was 4.11 (1.15-17.6) IU/dL.
Conclusions: Model-based estimates showed that a single dose of fidanacogene elaparvovec elicited long-lasting elevations in FIX activity, suggesting most individuals would not require prophylactic FIX replacement for at least 15 years post-infusion.
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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