Sweiss Karen, Quigley John G, Oh Annie, Lee Jonathan, Ye Rosa, Rondelli Damiano, Patel Pritesh
1 Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, USA.
2 Cancer Center, University of Illinois, Chicago, IL, USA.
J Oncol Pharm Pract. 2019 Jan;25(1):226-228. doi: 10.1177/1078155217729745. Epub 2017 Aug 31.
Busulfan is an alkylating agent used in pre-transplant conditioning for patients undergoing hematopoietic stem cell transplantation. Several factors contribute to variations in busulfan drug disposition including bioavailability, age, liver function, genetic polymorphisms, and concurrent administration of other drugs. Busulfan is metabolized by hepatic oxidation via the cytochrome P450 3A4 system as well as through conjugation with glutathione. Interactions with drugs such as phenytoin, itraconazole, and metronidazole have been reported to alter busulfan clearance and result in sub- or supra-therapeutic concentrations. We report a case of a clinically significant drug interaction between intravenous busulfan and the bifunctional T-cell engager, blinatumomab, observed through busulfan therapeutic drug monitoring. We found that busulfan clearance was reduced resulting in a higher area under the concentration-time curve when it was administered 48 h after blinatumomab. Repeat busulfan pharmacokinetic testing two weeks later demonstrated increased clearance of the drug and a 31% higher dose recommendation. Similar to other protein therapeutics, cytokine elevations during blinatumomab treatment can lead to cytochrome 3A4 suppression. We hypothesize that the increased busulfan levels observed could be related to a cytokine-mediated CYP3A4 suppression. This represents a unique pharmacologic consideration in hematopoietic stem cell transplantation which would impact several drugs that undergo CYP3A4 metabolism, including calcineurin inhibitors, cyclophosphamide, sirolimus, and triazole antifungals. Additionally, this mechanism of CYP3A4 suppression may be relevant in treatments and disease states where cytokine levels are elevated such as haploidentical stem cell transplantation, graft-versus-host disease, and use of chimeric antigen receptor T-cell therapy.
白消安是一种烷化剂，用于接受造血干细胞移植患者的移植前预处理。多种因素导致白消安药物处置的差异，包括生物利用度、年龄、肝功能、基因多态性以及其他药物的同时使用。白消安通过细胞色素P450 3A4系统进行肝脏氧化代谢，也通过与谷胱甘肽结合进行代谢。据报道，与苯妥英、伊曲康唑和甲硝唑等药物的相互作用会改变白消安的清除率，导致低于或高于治疗浓度。我们报告了一例通过白消安治疗药物监测观察到的静脉注射白消安与双功能T细胞衔接器blinatumomab之间具有临床意义的药物相互作用。我们发现，在blinatumomab给药48小时后给予白消安时，其清除率降低，导致浓度-时间曲线下面积更高。两周后重复进行白消安药代动力学测试，结果显示该药物的清除率增加，剂量推荐提高了31%。与其他蛋白质治疗药物类似，blinatumomab治疗期间细胞因子升高可导致细胞色素3A4抑制。我们推测，观察到的白消安水平升高可能与细胞因子介导的CYP3A4抑制有关。这代表了造血干细胞移植中一个独特的药理学考虑因素，会影响几种经CYP3A4代谢的药物，包括钙调神经磷酸酶抑制剂、环磷酰胺、西罗莫司和三唑类抗真菌药。此外，这种CYP3A4抑制机制可能在细胞因子水平升高的治疗和疾病状态中具有相关性，如单倍体相合干细胞移植、移植物抗宿主病以及嵌合抗原受体T细胞疗法的使用。
