Internal Medicine IX: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University, Medical Faculty Heidelberg/Heidelberg University Hospital, Heidelberg, Germany.
Internal Medicine V: Department of Hematology, Oncology and Rheumatology, Heidelberg University, Medical Faculty Heidelberg/Heidelberg University Hospital, Heidelberg, Germany.
Pharmacol Res Perspect. 2024 Jun;12(3):e1198. doi: 10.1002/prp2.1198.
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.
个体西罗莫司全血浓度差异很大，受细胞色素 P450（CYP）3A 诱导剂或抑制剂的伴随使用的严重影响，也受食物的影响。因此，建议进行治疗药物监测，特别是在治疗开始时或在可能影响西罗莫司暴露的情况下。在本病例报告中，我们强调了实现治疗性西罗莫司浓度的挑战，并提出了一些实用的解决方案，包括方案调整、药代动力学增强（使用药物相互作用）、浓度监测以及随后进行群体药代动力学建模，以支持治疗决策。在一名 69 岁的异基因造血干细胞移植女性患者中，西罗莫司浓度稳定，直到她发生伴有强直-阵挛性发作的脑弓形虫病。在治疗这种急性感染期间，西罗莫司浓度降至治疗范围以下，并且剂量增加对其影响不大。[2024 年 5 月 4 日更正：在前一句中，“tacrolimus concentrations”已更改为“sirolimus concentrations”。]只有同时给予 CYP3A4 抑制剂氟康唑并将西罗莫司给药间隔缩短至（非批准）每日两次给药，才能成功控制浓度，最终甚至可以减少剂量。这一干预措施使西罗莫司平均谷浓度增加到 5.85ng/ml，即达到了预期的目标范围。此外，在开始使用氟康唑后，西罗莫司谷浓度/每日剂量的比值从 26.9 增加到 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。这种策略可以推广到其他 CYP 抑制剂和其他治疗方案。
