Abstract | BACKGROUND AND OBJECTIVE: METHODS: We evaluated the effect of tucatinib on cardiac repolarization in healthy volunteers in a phase I, randomized, partially double-blind, placebo-and positive-controlled three-period crossover study. The primary endpoint was the placebo-corrected change from baseline in QT interval values, corrected for heart rate using Fridericia's method (ΔΔQTcF). RESULTS: After achieving steady-state tucatinib exposures with 300 mg twice daily, the observed ΔΔQTcF ranged from -2.9 msec at 2 hours post-dose to 0 msec at 4 hours post-dose. The upper bound of the 90% confidence interval (CI) was below 5 ms at all post-dose timepoints. Assay sensitivity was confirmed as the lower bound of the 90% CI and was >5 ms following moxifloxacin dosing. As the mean ΔΔQTcF of tucatinib was predicted to be - 1.80 ms (90% CI - 3.90, 0.30) at clinically relevant tucatinib concentrations (511 ng/mL), an effect of tucatinib on QTcF exceeding 10 ms was excluded within observed ranges of tucatinib (up to ~1000 ng/mL). Tucatinib had no clinically relevant effect on heart rate or cardiac conduction. The safety profile of tucatinib was manageable after multiple doses. CONCLUSION:
Tucatinib had no clinically relevant effects on studied ECG parameters. This study constitutes a clearly negative TQT study per ICH E14 guidance. CLINICAL TRIAL REGISTRATION: This trial (NCT03777761) was registered on 17 December 2018.
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Authors | Ariel R Topletz-Erickson, JoAl G Mayor, Hsu-Tai Liu, Layth I Abdulrasool, Christopher J Endres |
Journal | Drugs in R&D
(Drugs R D)
Vol. 23
Issue 4
Pg. 411-419
(Dec 2023)
ISSN: 1179-6901 [Electronic] New Zealand |
PMID | 37751113
(Publication Type: Randomized Controlled Trial, Clinical Trial, Phase I, Journal Article)
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Copyright | © 2023. The Author(s). |
Chemical References |
- tucatinib
- Fluoroquinolones
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Topics |
- Humans
- Electrocardiography
- Healthy Volunteers
- Cross-Over Studies
- Fluoroquinolones
- Dose-Response Relationship, Drug
- Double-Blind Method
- Heart Rate
- Long QT Syndrome
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