Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4 Perpetrators Using Physiologically Based Pharmacokinetic Modeling

Based on ibrutinib pharmacokinetics and potential sensitivity towards CYP3A4‐mediated drug–drug interactions (DDIs), a physiologically based pharmacokinetic approach was developed to mechanistically describe DDI with various CYP3A4 perpetrators in healthy men under fasting conditions. These models w...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2016-11, Vol.100 (5), p.548-557
Main Authors: de Zwart, L, Snoeys, J, De Jong, J, Sukbuntherng, J, Mannaert, E, Monshouwer, M
Format: Article
Language:English
Subjects:
Alkynes
Azithromycin - pharmacology
Benzoxazines - pharmacology
Carbamazepine - pharmacology
Cyclopropanes
Cytochrome P-450 CYP3A Inducers - pharmacology
Cytochrome P-450 CYP3A Inhibitors - pharmacology
Drug Dosage Calculations
Drug Interactions
Fluvoxamine
Humans
Ketoconazole - pharmacology
Male
Models, Biological
Pyrazoles - blood
Pyrazoles - pharmacokinetics
Pyrimidines - blood
Pyrimidines - pharmacokinetics
Rifampin - pharmacology
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Summary:Based on ibrutinib pharmacokinetics and potential sensitivity towards CYP3A4‐mediated drug–drug interactions (DDIs), a physiologically based pharmacokinetic approach was developed to mechanistically describe DDI with various CYP3A4 perpetrators in healthy men under fasting conditions. These models were verified using clinical data for ketoconazole (strong CYP3A4 inhibitor) and used to prospectively predict and confirm the inducing effect of rifampin (strong CYP3A4 inducer); DDIs with mild (fluvoxamine, azithromycin) and moderate inhibitors (diltiazem, voriconazole, clarithromycin, itraconazole, erythromycin), and moderate (efavirenz) and strong CYP3A4 inducers (carbamazepine), were also predicted. Ketoconazole increased ibrutinib area under the curve (AUC) by 24‐fold, while rifampin decreased ibrutinib AUC by 10‐fold; coadministration of ibrutinib with strong inhibitors or inducers should be avoided. The ibrutinib dose should be reduced to 140 mg (quarter of maximal prescribed dose) when coadministered with moderate CYP3A4 inhibitors so that exposures remain within observed ranges at therapeutic doses. Thus, dose recommendations for CYP3A4 perpetrator use during ibrutinib treatment were developed and approved for labeling.
ISSN:0009-9236
1532-6535
DOI:10.1002/cpt.419