Development of UPLC-MS/MS Method for Studying the Pharmacokinetic Interaction Between Dasatinib and Posaconazole in Rats

Abstract

Background and Aim

Dasatinib is approved for the treatment of leukaemia worldwide. Triazole agents such as posaconazole may be used for the control of secondary fungal infection with leukaemia. This work aimed to develop a bioanalytical method to study the potential interaction between dasatinib and posaconazole.

Methods

An ultrahigh-performance liquid chromatography-tandem mass spectrometry method was established to measure the plasma concentrations of dasatinib and posaconazole in rats simultaneously. Simple protein precipitation with acetonitrile was applied to extract dasatinib and posaconazole in samples. The chromatographic separation of analytes was conducted on an UPLC BEH C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Dasatinib and posaconazole were monitored in positive ion mode with the following mass transition pairs: m/z 488.2→401.1 for dasatinib and m/z 701.3→683.4 for posaconazole. The method was successfully applied for pharmacokinetic interaction between dasatinib and posaconazole.

Results

The established method expressed good linearity in 1–1000 ng/mL of dasatinib and 5–5000 ng/mL of posaconazole, with limit of detection was 1 ng/mL and 5 ng/mL, respectively. Methodology validations, including accuracy, precision, matrix effect, recovery, and stability, met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Dasatinib strongly inhibited the clearance of posaconazole in vivo, while posaconazole expressed no significant effect on the pharmacokinetics of dasatinib.

Conclusion

Dasatinib alters the pharmacokinetics of posaconazole. Attention should be paid to the unexpected risk of adverse clinical outcomes when posaconazole is co-administered with dasatinib.

Keywords:

• dasatinib
• posaconazole
• UPLC-MS/MS
• interaction
• pharmacokinetics

Acknowledgments

This work was supported by the Project Supported by Zhejiang Provincial Natural Science Foundation of China [grant number LYY19H310007] and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission [grant number 2018KY519].

Disclosure

The authors declare no conflicts of interest.