Sylvia D. Klomp, Anette Veringa, Jan-Willem C. Alffenaar, Mark G. J. de Boer, Lambert F. R. Span, Henk-Jan Guchelaar, Jesse J. Swen
{"title":"炎症改变了接受伏立康唑治疗的患者的 CYP2C19 基因型与 CYP2C19 活性之间的相关性。","authors":"Sylvia D. Klomp, Anette Veringa, Jan-Willem C. Alffenaar, Mark G. J. de Boer, Lambert F. R. Span, Henk-Jan Guchelaar, Jesse J. Swen","doi":"10.1111/cts.13887","DOIUrl":null,"url":null,"abstract":"<p>Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between <i>CYP2C19</i> genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, <i>CYP2C19</i> genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of <i>CYP2C19</i> genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their <i>CYP2C19</i> genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the <i>CYP2C19</i> genotypes.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13887","citationCount":"0","resultStr":"{\"title\":\"Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole\",\"authors\":\"Sylvia D. Klomp, Anette Veringa, Jan-Willem C. Alffenaar, Mark G. J. de Boer, Lambert F. R. Span, Henk-Jan Guchelaar, Jesse J. Swen\",\"doi\":\"10.1111/cts.13887\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between <i>CYP2C19</i> genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, <i>CYP2C19</i> genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of <i>CYP2C19</i> genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their <i>CYP2C19</i> genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the <i>CYP2C19</i> genotypes.</p>\",\"PeriodicalId\":50610,\"journal\":{\"name\":\"Cts-Clinical and Translational Science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-07-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13887\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cts-Clinical and Translational Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cts.13887\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cts-Clinical and Translational Science","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cts.13887","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole
Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.
期刊介绍:
Clinical and Translational Science (CTS), an official journal of the American Society for Clinical Pharmacology and Therapeutics, highlights original translational medicine research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease. Translational medicine is a multi-faceted discipline with a focus on translational therapeutics. In a broad sense, translational medicine bridges across the discovery, development, regulation, and utilization spectrum. Research may appear as Full Articles, Brief Reports, Commentaries, Phase Forwards (clinical trials), Reviews, or Tutorials. CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine. Best-in-class methodologies and best practices are also welcomed as Tutorials. These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science. CTS welcomes high quality, scientifically sound, original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of both traditional drugs and innovative modalities.