Effect of cyclosporine a and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation

Abstract

1. Voriconazole is known to display highly variable pharmacokinetics affecting treatment efficacy and safety. This study aimed to identify the factors causing the variation of voriconazole concentration in patients with allogeneic hematopoietic stem cell transplantation.

2. The data of patients was collected, including clinical characteristics and voriconazole concentrations. A total of 5 single nucleotide polymorphisms of 3 candidate genes (CYP2C19, ABCC2, ABCG2) related to voriconazole metabolism were genotyped by MassArray method. The correlation between polymorphisms and voriconazole concentration was analyzed.

3. A total of 244 voriconazole concentrations of 43 patients were included in this study. The voriconazole concentration was significantly correlated with patients' total bile acid (p = 0.001) and cyclosporin A (p < 0.001). The median concentration of the CYP2C19 normal metabolizers was remarkably lower than poor metabolizers (0.86 vs 2.27 μg/mL). The median concentration of ABCC2 rs2273697 GG genotype carriers was significantly higher than that of GA genotype carriers (p = 0.026).

4. The variability of voriconazole concentration is partially explained by total bile acid, metabolic types of CYP2C19. The voriconazole concentration of CYP2C19 normal metabolizers is likely to be lower than 1.0 μg/mL and thus at risk of infection due to inadequate treatment.

Keywords:

• Allogeneic hematopoietic stem cell transplantation
• voriconazole
• total bile acid
• cyclosporine A
• CYP2C19
• ABCC2

Acknowledgments

The authors thank all patients who contributed to this work. The authors also thank Professor Shusen Sun from College of Pharmacy and Health Science at Western New England University, USA, for his valuable advice.

Author contributions

Zanling Zhang and Jia Luo designed the study. Guang Ting Zeng performed the date analysis and wrote the manuscript. Lihong Shi, Huilan Li and Linlin Wang recruited patients. Miaomiao Zhu extracted the DNA.

Disclosure statement

The authors declared that they have no conflict of interests.

Additional information

Funding

This work was supported by a grant from the Natural Science Foundation of Hunan Province (no. 2017JJ2398).