The Pharmacokinetic Interaction of Tirabrutinib with Voriconazole, Itraconazole, and Fluconazole in SD Rats by UPLC-MS/MS

Title:The Pharmacokinetic Interaction of Tirabrutinib with Voriconazole, Itraconazole, and Fluconazole in SD Rats by UPLC-MS/MS

Volume: 31 Issue: 34

Author(s): Mengming Xia, Ya-Nan Liu, Jie Chen, Ren-Ai Xu*Gexin Dai*

Affiliation:

• The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

• The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Abstract:

Background: Tirabrutinib is an orally effective, approved, and highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor for the treatment of recurrent or refractory primary central nervous system lymphoma (PCNSL).

Objective: This study aimed to develop an ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) method for the determination of tirabrutinib concentration in rat plasma, where zanubrutinib was used as an internal standard (IS). This method was also applied to study whether tirabrutinib would interact with voriconazole, itraconazole, and fluconazole in rats, providing a reference value for clinical medication guidance.

Methods: In the current study, the organic solvent protein precipitation method was used to treat plasma samples, which is simple and reproducible. Tirabrutinib (m/z 455.32 → 320.21) and zanubrutinib (m/z 472.13 → 455.04) were separated on a Waters Acquity BEH C18 column (2.1 × 50 mm, 1.7 μm) and detected by multiple reaction monitoring (MRM) in positive ionization mode.

Results: The method showed good linearity in the range of 5−3000 ng/mL for tirabrutinib with the lower limit of quantification (LLOQ) of 5 ng/mL. The recovery and matrix effects were 85.7-91.0% and 102.0-113.3%, respectively. The accuracy, precision, stability, and carry-over effect were also acceptable. The method could also be used for determining the pharmacokinetic interaction of tirabrutinib in rats. The results showed AUC_0→∞ of tirabrutinib to be increased by 139.3% and 83.9% in the presence of voriconazole and fluconazole, respectively, while itraconazole had little effect.

Conclusion: It is necessary to monitor the concentration of tirabrutinib in patients when it is combined with voriconazole and fluconazole to achieve a better therapeutic effect and reduce the risk of adverse reaction. Further research should be conducted in the future.

Cite this article as:

Xia Mengming, Liu Ya-Nan, Chen Jie, Xu Ren-Ai*, Dai Gexin*, The Pharmacokinetic Interaction of Tirabrutinib with Voriconazole, Itraconazole, and Fluconazole in SD Rats by UPLC-MS/MS, Current Medicinal Chemistry 2024; 31 (34) . https://dx.doi.org/10.2174/0109298673268883231108062655