Surowiec Dorothy, DePestel Daryl D, Carver Peggy L
Department of Pharmacy Services, University of Michigan Health System, Ann Arbor, Michigan, USA.
Pharmacotherapy. 2008 Jun;28(6):719-29. doi: 10.1592/phco.28.6.719.
To assess the use and safety of concurrent administration of voriconazole and sirolimus-which is contraindicated-and to determine approaches for appropriately managing patients who receive both drugs.
Retrospective medical record review.
University-affiliated medical center.
Thirty-one cases in 23 inpatients who received at least one dose of voriconazole and sirolimus concomitantly within a 24-hour period.
Data on sirolimus and voriconazole indications, doses, routes, frequencies, and administration times; number of days of coadministration; and sirolimus dosage adjustments were collected. In addition, data on laboratory values, adverse events, sirolimus concentrations, and concomitant drugs, including cytochrome P450 (CYP) 3A isoenzyme and P-glycoprotein inhibitors and inducers, were collected for 7 days before, during, and for 14 days after coadministration. No cases of elevated sirolimus concentrations (>20 mg/ml) occurred in patients stabilized with voriconazole before starting low-dose sirolimus 0.5-1 mg/day, or in those stabilized with sirolimus 0.5-2 mg/day who had baseline sirolimus concentrations of 12 ng/ml or lower and whose sirolimus dose was decreased by 50% before the addition of voriconazole. In contrast, elevated sirolimus concentrations were experienced in patients receiving sirolimus doses of 4 mg/day or higher who had sirolimus concentrations of 12 ng/ml or higher and whose sirolimus dose was not decreased before addition of voriconazole. In a patient who received sirolimus with itraconazole, a strong CYP3A isoenzyme inhibitor, one case of only a minimal increase in the sirolimus concentration occurred after the addition of voriconazole.
Sirolimus and voriconazole can be safely coadministered as long as consideration is given to which agent the patient receives first, the sirolimus dosage, sirolimus concentrations, and concurrent disease states and CYP3A isoenzyme inhibitors. Sirolimus concentrations should be closely and routinely monitored before, during, and after coadministration of voriconazole and other CYP3A isoenzyme inhibitors. Based on the results of this pilot study, a protocol on the management of this drug combination will be implemented and prospectively evaluated for efficacy and safety.
评估伏立康唑与西罗莫司（禁忌联用）同时给药的使用情况及安全性，并确定对接受两种药物治疗的患者进行适当管理的方法。
回顾性病历审查。
大学附属医院。
23名住院患者中的31例，他们在24小时内至少同时接受了一剂伏立康唑和西罗莫司。
收集了西罗莫司和伏立康唑的适应证、剂量、给药途径、频率及给药时间；联合给药天数；以及西罗莫司剂量调整的数据。此外，还收集了联合给药前7天、给药期间及给药后14天的实验室检查值、不良事件、西罗莫司浓度及合并用药的数据，包括细胞色素P450（CYP）3A同工酶和P-糖蛋白抑制剂及诱导剂。在开始使用低剂量西罗莫司（0.5 - 1毫克/天）前已用伏立康唑稳定病情的患者中，或在使用西罗莫司（0.5 - 2毫克/天）且基线西罗莫司浓度为12纳克/毫升或更低、在加用伏立康唑前西罗莫司剂量降低50%的患者中，未出现西罗莫司浓度升高（>20毫克/毫升）的情况。相比之下，接受西罗莫司剂量为4毫克/天或更高、西罗莫司浓度为12纳克/毫升或更高且在加用伏立康唑前未降低西罗莫司剂量的患者，出现了西罗莫司浓度升高的情况。在一名接受西罗莫司与伊曲康唑（一种强效CYP3A同工酶抑制剂）治疗的患者中，加用伏立康唑后仅出现了一例西罗莫司浓度轻微升高的情况。
只要考虑患者先接受哪种药物、西罗莫司剂量、西罗莫司浓度、合并疾病状态及CYP3A同工酶抑制剂，西罗莫司和伏立康唑可以安全地联合使用。在伏立康唑及其他CYP3A同工酶抑制剂联合给药前、给药期间及给药后，应密切且定期监测西罗莫司浓度。基于这项初步研究的结果，将实施一项关于这种药物联合使用管理的方案，并对其疗效和安全性进行前瞻性评估。
