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Multiple Administrations of Itraconazole Increase Plasma Exposure to Pyrotinib in Chinese Healthy Adults
Yueyue Liu1, Qian Zhang1, Chao Lu1
1Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, People's Republic of China.
Purpose:
Pyrotinib, an irreversible human epidermal growth factor receptor 2 (HER2), is a epidermal growth factor receptor double-target tyrosine kinase inhibitor used for treating HER2-positive breast cancer. This study aimed to evaluate the impact of the strong CYP3A4 inhibitor itraconazole on the safety and pharmacokinetics of pyrotinib in Chinese healthy adults.
Patients And Methods:
This was an open-label, randomized, self-control study. Eighteen healthy adults were included in this trial. They received a single 80 mg dose of pyrotinib orally on days 1 and 9, and a 200 mg once-daily dose of itraconazole on days 6 through 22. Blood samples were obtained, and the drug concentration was detected using liquid chromatography/tandem mass spectrometry.
Results:
Compared with pyrotinib alone, the exposure to pyrotinib co-administered with itraconazole substantially increased, and the C max and AUC0-t increased by 2.78- and 10.8-fold, respectively. No serious adverse events were reported in this trial, and no participant dropped out of the trial because of adverse events.
Conclusion:
The exposure to pyrotinib was substantially affected by the action of itraconazole. The concomitant use of pyrotinib with itraconazole might require dose modification of pyrotinib. All treatments were well tolerated in healthy participants.
Clinical Trial Registry:
http://www.chinadrugtrials.org.cn/clinicaltrials.prosearch.dhtml, CTR20191866.
Insights
The strong CYP3A4 inhibitor itraconazole significantly increased pyrotinib exposure in healthy adults. Pyrotinib and itraconazole co-administration may require pyrotinib dose adjustments due to altered pharmacokinetics.
Area of Science:
- Pharmacology
- Oncology
- Clinical Pharmacology
Background:
- Pyrotinib is a tyrosine kinase inhibitor targeting HER2 for HER2-positive breast cancer.
- Drug interactions can affect treatment efficacy and safety.
Purpose of the Study:
- To assess the pharmacokinetic impact of itraconazole, a CYP3A4 inhibitor, on pyrotinib in Chinese healthy adults.
- To evaluate the safety profile of pyrotinib when co-administered with itraconazole.
Main Methods:
- An open-label, randomized, self-controlled study involving 18 healthy adults.
- Participants received single oral doses of pyrotinib (80 mg) and daily doses of itraconazole (200 mg).
- Drug concentrations were measured using liquid chromatography/tandem mass spectrometry.
Main Results:
- Co-administration with itraconazole substantially increased pyrotinib exposure, with Cmax rising 2.78-fold and AUC0-t increasing 10.8-fold.
- No serious adverse events were reported.
- No participants withdrew due to adverse events.
Conclusions:
- Itraconazole significantly alters pyrotinib pharmacokinetics, increasing its exposure.
- Potential dose modification of pyrotinib may be necessary when used concurrently with itraconazole.
- The combination was well-tolerated in healthy participants.
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