The Effect of Yinchenhao Decoction on the Pharmacokinetic Profile of Futibatinib by HPLC-MS/MS

Abstract

Futibatinib is an excellent fibroblast growth factor receptor 1–4 (FGFR 1–4) inhibitor that exhibits selective anti-tumor activeness against FGFR-deregulated tumors. A new high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique for the quantitative analysis of futibatinib in beagle dog plasma was developed, and the effect of Yinchenhao decoction (YCHD) on the pharmacokinetics of futibatinib was evaluated. After processing plasma samples with ethyl acetate extraction in the alkaline condition of sodium carbonate, a C18 column (4.6 mm × 150, 5 μm) was used to accomplish the separation of futibatinib and ripretinib (internal standard, ISTD), with the mobile phase consisting of methanol and 0.1% formic acid in water (60:40). The scanning method adopted a multiple reaction monitoring (MRM) mode with positive ion detection through the triple quadrupole mass spectrometer. The ion transitions for futibatinib and IS were m/z 419.20 → 296.15 and m/z 510.36 → 417.00, respectively. Futibatinib displayed excellent linearity in the range of 1–200 ng/mL. Neither inter-day nor intra-day precision exceeded 6.3%. The %RE values for accuracy ranged from −3.1% to 0.9%. The recovery, stability, and matrix effect of futibatinib also complied with the guidelines for the validation of quantitative analysis methods for biological samples in the 2020 edition of the Chinese Pharmacopoeia. In combination with YCHD, the Cmax of futibatinib increased by 40.84% compared to futibatinib dosage alone., and the AUC(0–t) and AUC(0–∞) of futibatinib increased by 78.06% and 82.71%, respectively. The Vd and CL of futibatinib were reduced by 20.05% and 40.85%, respectively. T1/2 was extended from 3.88 h to 5.26 h. The results indicated that YCHD could affect the pharmacokinetics of futibatinib and increase the plasma exposure of futibatinib. If YCHD is administered along with futibatinib, this study gives a first impression how pharmacokinetics and toxicokinetics would change.