Home Blog of Signal Transduction Protein Tyrosine Kinase BTK Itraconazole increases ibrutinib exposure ten-fold and reduces inter-individual variation - A potentially beneficial drug-drug interaction

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Itraconazole increases ibrutinib exposure ten-fold and reduces inter-individual variation - A potentially beneficial drug-drug interaction

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by CYP3A4. 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 AUC0-∞ of ibrutinib 10.0-fold (90% CI 7.2-13.9; P < 0.001) and Cmax 8.8-fold (90% CI 6.3-12.1; P < 0.001). During itraconazole, the inter-subject variation for the AUC0-∞ (55%) and Cmax (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its inter-individual variability, offering a possibility to improved dosing accuracy and cost savings.

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Cat.No. Product Name Information
S2680 Ibrutinib Ibrutinib is a potent and highly selective Brutons tyrosine kinase (Btk) inhibitor with IC50 of 0.5 nM in cell-free assays, modestly potent to Bmx, CSK, FGR, BRK, HCK, less potent to EGFR, Yes, ErbB2, JAK3, etc. Ibrutinib is applicable as a Btk ligand in the synthesis of a series of PROTACs including P13I.

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BTK