个体西罗莫司全血浓度变化很大,受伴随使用细胞色素P450(CYP)3A诱导剂或抑制剂的严重影响,也受食物调节。因此,建议进行治疗药物监测,尤其是在治疗开始时或在可能影响西罗莫司暴露的情况下。在这个案例报告中,我们强调了实现治疗性西罗莫司浓度的挑战,并提出了具有方案适应的实用解决方案,药代动力学增强(使用药物-药物相互作用),浓度监测,以及随后的群体药代动力学建模,以支持治疗决策。一名69岁女性异基因造血干细胞移植患者,他克莫司浓度稳定,直到她发展为脑弓形虫病并伴有强直阵挛性癫痫发作。在治疗这种急性感染期间,他克莫司浓度下降至亚治疗水平,且基本不受剂量增加的影响.只有同时施用CYP3A4抑制剂氟康唑和将西罗莫司给药间隔缩短至每天两次(未经批准)才能成功控制浓度,最终甚至使剂量减少成为可能。这种干预导致西罗莫司平均谷浓度增加至5.85ng/mL,即,进入所需的目标范围。此外,开始使用氟康唑后,西罗莫司谷水平/日剂量的比例从26.9ng/mL/mg/kg/天提高到109ng/mL/mg/kg/天.因此,本病例报告描述了使用临床药理学概念和药代动力学模型来优化个体患者的治疗策略.该策略可以推广到其他CYP抑制剂和其他治疗方案。
Individual
sirolimus whole blood concentrations are highly variable, critically influenced by the concomitant use of cytochrome P450 (CYP) 3A inducers or inhibitors, and also modulated by food. Therapeutic drug monitoring is therefore recommended, especially at treatment start or in circumstances that can influence sirolimus exposure. In this
case report, we highlight the challenge of achieving therapeutic
sirolimus concentrations and present pragmatic solutions with regimen adaptions, pharmacokinetic enhancement (use of a drug–drug interaction), concentration monitoring, and subsequent modeling of population pharmacokinetics to support treatment decisions. In a 69-year-old female patient with allogeneic hematopoietic stem cell transplantation, sirolimus concentrations were stable until she developed cerebral toxoplasmosis with tonic–clonic seizures. During treatment of this acute infection,
sirolimus concentrations dropped to subtherapeutic levels and remained largely unaffected by dose increases. [Correction added on 4 May 2024, after first online publication: The word “tacrolimus concentrations” has been changed to “sirolimus concentrations” in the preceding sentence.] Only the simultaneous administration of the CYP3A4 inhibitor fluconazole and a shortening of the sirolimus dosing intervals to a (non-approved) twice-daily administration led to successful control of the concentrations, which ultimately even made a dose reduction possible. This intervention resulted in an increase of
sirolimus mean trough concentration to 5.85 ng/mL, i.e., into the desired target range. Additionally, a higher ratio of sirolimus trough levels/daily dose from 26.9 to 109 ng/mL/mg/kg/day was achieved with the initiation of fluconazole. Thus, this
case report describes the use of clinical pharmacological concepts and pharmacokinetic modeling to optimize treatment strategies in an individual patient. This strategy could be generalized to other CYP inhibitors and other treatment regimens.