부산대학교 도서관

Tacrolimus, a CYP3A4 substrate with a narrow therapeutic index, requires dose adjustment when used with voriconazole, a potent CYP3A4 inhibitor. Recent reports separately describe interactions involving flucloxacillin and tacrolimus or voriconazole, resulting in decreased concentrations of these drugs individually. It has been suggested that tacrolimus concentrations are unaffected by flucloxacillin when voriconazole is used, however this has not been extensively investigated. A retrospective review of voriconazole and tacrolimus concentrations and subsequent dose adjustment following flucloxacillin administration. Data are reported as median and interquartile range [IQR]. 8 patients (5 lung transplant, 2 re-do lung transplant, 1 heart transplant) received concurrent tacrolimus, flucloxacillin and voriconazole. For voriconazole, 3 of the 8 patients had concentrations measured prior to flucloxacillin initiation; all 3 were therapeutic. Following flucloxacillin initiation, all 8 patients exhibited sub-therapeutic concentrations, with a median concentration of 0.15mg/L [IQR 0.10-0.28]. In 5 patients, concentrations remained sub-therapeutic despite voriconazole dose increases; 2 patients were changed to alternative antifungal agents. For tacrolimus, after flucloxacillin initiation, all patients required dose increases to maintain therapeutic concentrations; the median total daily dose prior to flucloxacillin was 3.5mg [IQR 2.0-4.3] and increased to 11.5mg [IQR 7.5-20] (P=0.0026). On ceasing flucloxacillin, the total daily dose reduced to 2.2mg [IQR 1.9-4.7]. Supra-therapeutic tacrolimus concentrations were observed in 7 of the 8 patients following flucloxacillin discontinuation (median concentration 19.7ug/L [IQR 17.9-28.0]. We demonstrate a significant interaction between flucloxacillin, voriconazole and tacrolimus, resulting in sub-therapeutic voriconazole concentrations, and requiring a substantial tacrolimus dose increase. Use of flucloxacillin in patients receiving voriconazole should be avoided. Tacrolimus concentrations should be closely monitored, and dosing adjusted, during and after flucloxacillin treatment. [ABSTRACT FROM AUTHOR]