The effect of rifampin on the pharmacokinetics of famitinib in healthy subjects.
Background: Famitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. As famitinib is metabolized mainly by cytochrome P450 3A4 (CYP3A4), the study was conducted to investigate the effect of potent CYP3A4 inducer ri...
| Publicado en: | Cancer Chemotherapy & Pharmacology Vol. 90; no. 5; pp. 409 - 416 |
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| Autores principales: | , , , , , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
Springer Nature
Nov2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=159631827&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 159631827 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03445704 NO9 jtl: Cancer Chemotherapy & Pharmacology issn: 03445704 maglogo: N pubinfo: dt: Nov2022 vid: 90 iid: 5 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 159631827 159122133 159631827 NLM36107220 10.1007/s00280-022-04474-8 NLM36107220 159631827 ppf: 409 ppct: 7 formats: tig: atl: The effect of rifampin on the pharmacokinetics of famitinib in healthy subjects. aug: au: Li, Ting Li, Xin Jiang, Xin Wang, Chenjing Sun, Feifei Liu, Yanping Lin, Pingping Shi, Ping Fu, Yao Gao, Xiaomeng Zhang, Yanyan Cao, Yu affil: Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, 266003, Qingdao, China sug: subj: Rifampin Oxidoreductases Pharmacodynamics Protein Kinase Inhibitors Adverse Effects Pharmacokinetics Oxidoreductases Metabolism Heterocyclic Compounds Male Drug Interactions Mass Spectrometry Indoles Protein Kinase Inhibitors Pharmacokinetics Research Subjects Chromatography, Liquid Scales Male ab: Background: Famitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. As famitinib is metabolized mainly by cytochrome P450 3A4 (CYP3A4), the study was conducted to investigate the effect of potent CYP3A4 inducer rifampin on the pharmacokinetics of famitinb.Methods: This single-center, single-arm and fixed-sequence drug-drug interaction study enrolled 21healthy Chinese male subjects. Subjects received a single oral dose of famitinib 25 mg on days 1 and 16 and repeated administration of oral rifampin 600 mg once daily on days 10-23. Blood samples were collected and plasma concentrations of famitinib were measured by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated using noncompartmental analysis and safety was assessed.Results: In the presence of rifampin, the famitinib geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) decreased by 48% and 69%, respectively, and the mean elimination half-life was shortened from 33.9 to 18.2 h. The geometric mean ratio (GMR) of famitinib Cmax and AUC0-∞ and their 90% CI were 0.52 (0.50, 0.54) and 0.31 (0.29, 0.33). Single dose of famitinib 25 mg was well tolerated and eight subjects (38.1%) reported treatment emergent adverse events, which were all grade 1-2 in severity.Conclusion: Co-administration of rifampin considerably reduces plasma concentration of famitinb due to CYP3A4 induction. Concomitant administration of famitinib and strong CYP3A4 inducers should be avoided, whereas when simultaneous use with inducers of CYP3A4, dose adjustment of famitinb is recommended.Clinical Trial Registration Number: NCT04494659 (July 31, 2020). pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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