Evaluation of the drug-drug interaction potential of brigatinib using a physiologically-based pharmacokinetic modeling approach
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Updated: Jul 4, 2025
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Published on: October 23, 2019
Michael J Hanley1, Karen Rowland Yeo2, Meera Tugnait3
1Clinical Pharmacology, Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA.
Abstract:
Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically-based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration-time curve from time 0 to infinity [AUC∞] ratio [with/without itraconazole]: predicted 1.86; observed 2.01) and rifampin (AUC∞ ratio [with/without rifampin]: predicted 0.16; observed 0.20). Simulations using the developed model predicted that moderate CYP3A inhibitors (e.g., verapamil and diltiazem) may increase brigatinib AUC∞ by ~40%, whereas moderate CYP3A inducers (e.g., efavirenz) may decrease brigatinib AUC∞ by ~50%. Simulations of potential transporter-mediated DDIs predicted that brigatinib may increase systemic exposures (AUC∞) of P-gp substrates (e.g., digoxin and dabigatran) by 15%-43% and MATE1 substrates (e.g., metformin) by up to 29%; however, negligible effects were predicted on BCRP-mediated efflux and OCT1-mediated uptake. The PBPK analysis results informed dosing recommendations for patients receiving moderate CYP3A inhibitors (40% brigatinib dose reduction) or inducers (up to 100% increase in brigatinib dose) during treatment, as reflected in the brigatinib prescribing information.
Insights
Brigatinib drug interactions were predicted using a pharmacokinetic model. The model accurately forecasted clinical data and informed dosing adjustments for moderate CYP3A inhibitors or inducers.
Area of Science:
- Pharmacology
- Drug Metabolism and Pharmacokinetics
- Oncology
Background:
- Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor for ALK-positive metastatic non-small cell lung cancer.
- In vitro studies identified brigatinib's primary metabolizing enzymes (CYP2C8, CYP3A4) and transporter interactions (P-gp, BCRP, OCT1, MATE1, MATE2K).
- Clinical studies confirmed CYP3A4's significant role in brigatinib clearance.
Purpose of the Study:
- To develop a physiologically-based pharmacokinetic (PBPK) model for brigatinib.
- To predict drug-drug interactions (DDIs) involving brigatinib with moderate CYP3A inhibitors/inducers and transporter substrates.
- To inform brigatinib dosing recommendations based on PBPK model predictions.
Main Methods:
- Development of a PBPK model for brigatinib.
- Validation of the PBPK model using clinical DDI data with strong CYP3A inhibitor (itraconazole) and inducer (rifampin).
- Simulation of brigatinib's PK in the presence of moderate CYP3A inhibitors/inducers and its effect on transporter substrates.
Main Results:
- The PBPK model accurately predicted clinical DDIs with itraconazole and rifampin.
- Simulations predicted moderate CYP3A inhibitors could increase brigatinib exposure by ~40%, while inducers could decrease it by ~50%.
- Brigatinib was predicted to increase exposure of P-gp substrates (15-43%) and MATE1 substrates (up to 29%), with minimal effects on BCRP and OCT1 substrates.
Conclusions:
- The PBPK model is a reliable tool for predicting brigatinib DDIs.
- Predicted DDIs support current dosing recommendations for brigatinib with moderate CYP3A modulators.
- The findings enhance understanding of brigatinib's pharmacokinetic profile and potential interactions.
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