Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction

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Tapaninen , T , Olkkola , A M , Tornio , A , Neuvonen , M , Elonen , E , Neuvonen , P J , Niemi , M & Backman , J T 2020 , ' Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction ' , Clinical and translational science , vol. 13 , no. 2 , pp. 345-351 . https://doi.org/10.1111/cts.12716

Title: Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction
Author: Tapaninen, Tuija; Olkkola, Aleksi M.; Tornio, Aleksi; Neuvonen, Mikko; Elonen, Erkki; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T.
Contributor: University of Helsinki, HUSLAB
University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
University of Helsinki, HUS Comprehensive Cancer Center
University of Helsinki, Medicum
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
Date: 2020-03
Number of pages: 7
Belongs to series: Clinical and translational science
ISSN: 1752-8054
URI: http://hdl.handle.net/10138/313607
Abstract: The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2-4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose-adjusted geometric mean area under the concentration-time curve from zero to infinity (AUC(0-infinity)) of ibrutinib 10.0-fold (90% confidence interval (CI) 7.2-13.9; P <0.001) and peak plasma concentration (C-max) 8.8-fold (90% CI 6.3-12.1; P <0.001). During itraconazole, the intersubject variation for the AUC(0-infinity) (55%) and C-max (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its interindividual variability, offering a possibility to improved dosing accuracy and cost savings.
Subject: 3111 Biomedicine
317 Pharmacy
ibrutinib
itraconazole
CYP3A4
drug-drug interaction
pharmacokinetic booster
PROPHYLAXIS
TYROSINE KINASE INHIBITOR
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