Department of Pharmacology and Toxicology, American University of Beirut, Faculty of Medicine, Beirut, Lebanon.
Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut, Faculty of Medicine, Beirut, Lebanon.
Curr Res Transl Med. 2020 Apr;68(2):51-58. doi: 10.1016/j.retram.2020.02.001. Epub 2020 Feb 22.
To evaluate polymorphisms in genes of drug metabolizing enzymes and transporters involved in cyclosporine and/or voriconazole disposition among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT).
DNA from forty patients was genotyped using the DMETPlus array. The average ratio of cyclosporine concentration/dose (C/D in (ng/mL)/(mg/kg)) per participant's weight was computed using available trough levels and daily doses.
The C/D cyclosporine ratio was significantly higher when it was administered with voriconazole as compared to when it was administered alone: median: 116.75 vs. 25.40 (ng/mL)/(mg/kg) with and without voriconazole respectively, (P < 0.001). There was also a significant association between the C/D cyclosporine ratio combined with voriconazole and the ABCB1 2677 G > T > A (rs2032582) genetic polymorphism (P = 0.05). In parallel, ABCB1 variant allele carriers had higher creatinine in combination therapy with a median creatinine (mg/dL) of 0.74 vs. 0.56 for variant allele carriers vs. reference; P = 0.003. Interestingly, CYP2C9, CYP2C19, and CYP3A5 extensive metabolizers tended to be associated with lower cyclosporine C/D ratio when combined with voriconazole, but the results were not statistically significant.
To the best of our knowledge, this is the first pharmacogenetic study on the interaction between voriconazole and cyclosporine in patients undergoing allo-HCT. Results suggest that the ABCB1 2677 G > T > A genetic polymorphism plays a role in this interaction with cyclosporine related nephrotoxicity. Pre-emptive genotyping for this genetic variant may be warranted for cyclosporine dose optimization. Larger studies are needed to potentially show significant associations with more candidate genes such as CYP3A4/5, CYP2C9, and CYP2C19, among others.
评估参与异基因造血细胞移植（allo-HCT）的患者中环孢素和/或伏立康唑处置相关药物代谢酶和转运体基因的多态性。
使用 DMETPlus 阵列对 40 名患者的 DNA 进行基因分型。根据可用的谷浓度和每日剂量，计算每个参与者体重的环孢素浓度/剂量（C/D，以（ng/mL）/（mg/kg）计）的平均值。
与单独使用环孢素相比，当与伏立康唑联合使用时，环孢素的 C/D 比值明显更高：中位数：116.75 与 25.40（ng/mL）/（mg/kg）分别与伏立康唑和无伏立康唑，（P < 0.001）。当将环孢素与伏立康唑联合使用时，C/D 环孢素比值与 ABCB1 2677G>T>A（rs2032582）遗传多态性之间也存在显著关联（P = 0.05）。同时，ABCB1 变体等位基因携带者在联合治疗时肌酐更高，中位数肌酐（mg/dL）为 0.74 与变体等位基因携带者与参考相比; P = 0.003。有趣的是，当与伏立康唑联合使用时，CYP2C9、CYP2C19 和 CYP3A5 广泛代谢物倾向于与较低的环孢素 C/D 比值相关，但结果无统计学意义。
据我们所知，这是第一项关于 allo-HCT 患者中伏立康唑与环孢素相互作用的药物遗传学研究。结果表明，ABCB1 2677G>T>A 遗传多态性在与环孢素相关肾毒性的这种相互作用中起作用。可能需要对这种遗传变异进行预先基因分型，以优化环孢素剂量。需要更大的研究来显示与其他候选基因（如 CYP3A4/5、CYP2C9 和 CYP2C19 等）的潜在显著关联。
