Related Experiment Video
Updated: Sep 2, 2025
Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Evaluation of Safety and Clinically Relevant Drug-Drug Interactions with Tucatinib in Healthy Volunteers
Ariel Topletz-Erickson1, Anthony Lee2, Evelyn L Rustia3,4
1Clinical Pharmacology and Pharmacometrics, Seagen Inc., 21823 30th Drive SE, Bothell, WA, 98021, USA.
Background And Objective:
Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.
Methods:
Parts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).
Results:
Tucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC0-inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs.
Conclusion:
The potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.
Trial Registration:
This trial (NCT03723395) was registered on October 29, 2018.
Insights
Tucatinib is primarily metabolized by CYP2C8 and inhibits CYP3A, impacting drug interactions. Dosing adjustments are recommended when co-administering tucatinib with certain CYP inducers, inhibitors, or substrates.
Area of Science:
- Pharmacology and Oncology
- Drug Metabolism and Pharmacokinetics
- Clinical Pharmacology
Background:
- Tucatinib is approved for HER2-positive metastatic breast cancer.
- Understanding drug-drug interactions (DDIs) is crucial for safe and effective tucatinib co-administration.
- This study evaluated potential DDIs involving tucatinib, metabolizing enzymes, and transporters.
Purpose of the Study:
- To assess the impact of CYP3A4 and CYP2C8 modulators on tucatinib pharmacokinetics.
- To evaluate tucatinib's effect on substrates of CYP2C8, CYP2C9, CYP3A4, and P-glycoprotein.
- To characterize the pharmacokinetic profile of tucatinib and its metabolite ONT-993 in the presence of interacting drugs.
Main Methods:
- Healthy volunteers received tucatinib with itraconazole (CYP3A4 inhibitor), rifampin (CYP inducer), or gemfibrozil (CYP2C8 inhibitor).
- The effect of tucatinib on repaglinide, tolbutamide, midazolam, and digoxin pharmacokinetics was assessed.
- Pharmacokinetic parameters, including AUC0-inf, were analyzed to determine interaction effects.
Main Results:
- Tucatinib is primarily metabolized by CYP2C8 and to a lesser extent by CYP3A.
- Tucatinib significantly increased midazolam exposure (5.7-fold), indicating strong CYP3A inhibition.
- Tucatinib showed weak inhibition of CYP2C8 and P-glycoprotein, with no impact on CYP2C9.
Conclusions:
- Tucatinib is a strong CYP3A inhibitor and primarily metabolized by CYP2C8.
- Recommendations include avoiding strong CYP3A inducers and considering dose adjustments for CYP3A substrates with narrow therapeutic windows.
- Caution is advised with strong CYP2C8 inhibitors and moderate CYP2C8 inducers; dose reduction of P-glycoprotein substrates may be necessary.
Related Concept Videos
01:13Therapeutic Index
01:09Factors Affecting Renal Clearance: Drug Distribution and Drug Interactions
One important factor is the relationship between renal clearance and the apparent volume of distribution. Renal clearance tends to be inversely proportional to the apparent volume of distribution. Drugs with an extensive distribution volume or those...
01:23Factors Affecting Protein-Drug Binding: Drug Interactions
Displacement interactions can have varying outcomes, ranging from toxicity to virtually...
01:26Drug Administration and Therapy Phases: Overview
The pharmaceutical phase focuses on leveraging the physicochemical properties of the drug to design and manufacture an effective product. Variants include orally administered tablets or capsules, topical creams or ointments, and parenteral-delivery solutions or emulsions.
The pharmacokinetic phase...