In vivo Pharmacokinetic Drug-Drug Interaction Studies Between Fedratinib and Antifungal Agents Based on a Newly Developed and Validated UPLC/MS-MS Method.

Congrong Tang,Guanyang Lin,Ren-Ai Xu,Xiaohui Niu,Lu Shi,Huidan Zhu

doi:10.3389/fphar.2020.626897

Abstract

In the current research experiment, a sensitive, precise and rapid bioanalytical approach involving the detection of fedratinib concentrations in rat plasma by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique was optimized and established, and it was employed to describe the changes of fedratinib concentrations after oral treatment with various antifungal drugs (isavuconazole, posaconazole, fluconazole and itraconazole). An Acquity UPLC BEH reverse-phase C18 column (2.1 mm × 50 mm, 1.7 μm) was used for chromatographic separation of fedratinib and bosutinib (as internal standard (IS) in our study) under a linear gradient elution of the mobile phase, which was composed of solution A (acetonitrile) and solution B (water with 0.1% formic acid), along with 0.40 ml/min flow rate. The analyte and internal standard were measured with electrospray ion source in positive ion mode on a XEVO TQS triple quadrupole tandem mass spectrometer. The newly developed UPLC-MS/MS assay displayed enough linearity within the concentration range of 0.5–500 ng/ml for calibration curve. The intra- and inter-day of precision and accuracy were evaluated and validated to meet the requirements for the guidelines of bioanalytical assay. In addition, the findings of matrix effect, recovery, and stability were all within the acceptable limits. The new UPLC-MS/MS method was also successfully applied to characterize the pharmacokinetic changes of fedratinib in rats in the present of different antifungal drugs (such as isavuconazole, posaconazole, fluconazole and itraconazole). It turned out that fluconazole resulted in a prominent inhibitory effect on fedratinib metabolism in rats, followed by treatment with itraconazole and isavuconazole. Therefore, the toxicity of fedratinib should be avoided when the concurrent use of fedratinib with CYP3A4 inhibitors may occur.

Highlights

Fedratinib (Figure 1A), a selective Janus kinase (JAK) two inhibitor used orally, has been developed for the therapy of myelofibrosis (MF) (Bewersdorf et al, 2019)
Significant improvement in symptoms and shrinkage of spleen were observed from placebo-controlled, randomized phase II and III clinical trials (Pardanani et al, 2015a; Pardanani et al, 2015b; Harrison et al, 2017; Blair, 2019), the first global approval of fedratinib was received by the United States Food and Drug Administration (FDA) for the therapy of intermediate-2 or highrisk primary or secondary MF in adult patients based on these favorable results
Fedratinib was proposed as an ideal drug for preventing the deteriorating outcomes of TH17 related with cytokine storm in COVID-19 and other severe viral infections (Wu and Yang, 2020)

Summary

Introduction

Fedratinib (Figure 1A), a selective Janus kinase (JAK) two inhibitor used orally, has been developed for the therapy of myelofibrosis (MF) (Bewersdorf et al, 2019). Fedratinib is mainly metabolized by CYP3A4, which plays an important role in many drug-drug interactions (DDIs). To the best of our knowledge, only one analytical assay for the measurement of fedratinib in biological matrices by liquid chromatography tandem mass spectrometry (LC-MS/MS) have been reported. It required complicated sample preparation procedure (more than 25 min), and high sample volumes (400 μL) (Ayesha Begum et al, 2020). This chromatography method of UPLC-MS/MS cannot effectively meet the requirement of high sample throughput for biological analysis in drug-drug interaction studies. A bioanalytical method developed following the latest United States FDA guideline for the validation of bioanalytical assays is necessary (Mei et al, 2019; Qiu et al, 2019)

Methods

Results

Conclusion