Nakagita Kazuki, Wada Kyoichi, Terada Yuka, Matsuda Sachi, Terakawa Nobue, Oita Akira, Takada Mitsutaka
Int J Clin Pharmacol Ther. 2018 Jun;56(6):270-276. doi: 10.5414/CP203209.
Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been used in combination with calcineurin inhibitors (tacrolimus and cyclosporine) to prevent allograft rejection following organ transplantation. In heart transplant recipients, everolimus should be maintained at a target blood concentration of 3 - 8 ng/mL, in combination with reduced-dose calcineurin inhibitors and therefore, requires strict monitoring. Fluconazole, an azole antifungal agent, affects blood concentration of tacrolimus by inhibiting the cytochromes P450 (CYP) 3A4 and 3A5. Therefore, to avoid overexposure during everolimus-azole cotreatment, the dose of everolimus should be reduced. However, the mechanism of interaction between everolimus and fluconazole remains unclear.
We report the case of a heart transplant recipient who experienced a 2.8-fold increase in everolimus clearance and a 3.5-fold increase in everolimus dosage, following withdrawal of fluconazole therapy. The clearance and dosage of tacrolimus increased 4.7- and 3.0-fold, respectively.
CONCLUSION: The concentrations of everolimus and tacrolimus should be carefully monitored when administered concomitantly with fluconazole to heart transplant recipients. The patient in this case had a CYP3A5*1/*3 genotype, and CYP3A5 constituted the metabolic pathway. Therefore, concomitant use of fluconazole might have a relatively small impact on everolimus and tacrolimus pharmacokinetics in this case. .
依维莫司是一种哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，已与钙调神经磷酸酶抑制剂（他克莫司和环孢素）联合用于预防器官移植后的同种异体移植排斥反应。在心脏移植受者中，依维莫司应与低剂量钙调神经磷酸酶抑制剂联合使用，维持目标血药浓度为3 - 8 ng/mL，因此需要严格监测。氟康唑是一种唑类抗真菌药，通过抑制细胞色素P450（CYP）3A4和3A5来影响他克莫司的血药浓度。因此，为避免依维莫司与唑类药物联合治疗期间药物暴露过量，应减少依维莫司的剂量。然而，依维莫司与氟康唑之间的相互作用机制仍不清楚。
我们报告了一例心脏移植受者的病例，该患者在停用氟康唑治疗后，依维莫司清除率增加了2.8倍，依维莫司剂量增加了3.5倍。他克莫司的清除率和剂量分别增加了4.7倍和3.0倍。
在心脏移植受者中，依维莫司和他克莫司与氟康唑联合使用时，应仔细监测其血药浓度。该病例中的患者具有CYP3A5*1/*3基因型，CYP3A5构成了代谢途径。因此，在这种情况下，氟康唑的联合使用可能对依维莫司和他克莫司的药代动力学影响相对较小。
