Department of Pharmacy, Institut de Cancérologie de Lorraine (ICL), Vandœuvre-lès-Nancy, France.
Data Biostatistics Unit, Institut de Cancérologie de Lorraine (ICL), Vandœuvre-lès-Nancy, France.
J Clin Pharm Ther. 2019 Jun;44(3):372-380. doi: 10.1111/jcpt.12823. Epub 2019 Mar 4.
Two forms of ifosfamide are commercially available in France: HOLOXAN® (brand-name drug) and IFOSFAMIDE EG® (generic drug). Following the marketing launch of the generic drug, there has been a significant increase in cases of ifosfamide-induced encephalopathy reported in France. Our objective is to compare the incidence of ifosfamide-induced encephalopathy in adult patients treated with HOLOXAN® or IFOSFAMIDE EG®.
This is a retrospective study of adult patients treated with ifosfamide in two medical centers from 2013 to 2017, with data analysed from medical records. Comparisons of patients were made, according to the formulation used and according to the occurrence of ifosfamide-induced encephalopathy. The groups of patients were compared using a chi-square or Fisher's exact test for qualitative parameters and a Wilcoxon test for quantitative parameters. To include confounding factors in the analysis of the impact of drug formulation on the occurrence of ifosfamide-induced encephalopathy, a generalized linear model was performed with the occurrence of ifosfamide-induced encephalopathy as the dependent parameter, and the formulation and the confounding factors as explanatory parameters.
A total of 191 patients were included: 103 patients received HOLOXAN® (53.9%) and 88 patients received IFOSFAMIDE EG® (46.1%). In the HOLOXAN® group, the median infusion time was higher (12 hours vs 3h, P < 0.001) and aprepitant was administered more frequently (78.6% vs 69.7%, P < 0.001) than for the IFOSFAMIDE EG® group. Ifosfamide-induced encephalopathy occurred in 11 patients (5.8%, CI 95% [2.9%, 10.0%]). In the ifosfamide-induced encephalopathy group, median infusion time was higher (12 hours [12; 24] vs 3 hours [2; 12] P < 0.001) and a poor performance status was more frequent (54.5% vs 13.9%, P = 0.002) than in the group without ifosfamide-induced encephalopathy. The frequency of ifosfamide-induced encephalopathy in the HOLOXAN® group was 1.9% (2/103) against 10.2% (9/88) in the IFOSFAMIDE EG® group (P = 0.014). Multivariate analysis revealed that treatment with IFOSFAMIDE EG® resulted in significantly more ifosfamide-induced encephalopathies compared to HOLOXAN® (OR and CI 95%:7.4 [1.4; 39.5], P = 0.018). We identified two other risk factors for ifosfamide-induced encephalopathy: long-term infusion and a performance status of two or higher.
The formation of chloroethylamine in solution could be the cause of more frequent ifosfamide-induced encephalopathies with IFOSFAMIDE EG® compared to HOLOXAN®. Application of these data could help in the choice of ifosfamide formulation in adult patients to decrease the risk of ifosfamide-induced encephalopathy, and more specifically for patients with risk factors.
法国市售两种异环磷酰胺制剂：HOLOXAN®（商品名药物）和 IFOSFAMIDE EG®（仿制药）。仿制药上市后，法国报告的异环磷酰胺引起的脑病病例显著增加。我们的目的是比较 HOLOXAN®和 IFOSFAMIDE EG®治疗的成年患者中异环磷酰胺引起的脑病的发生率。
这是一项回顾性研究，纳入了 2013 年至 2017 年在两个医学中心接受异环磷酰胺治疗的成年患者，数据来自病历。根据使用的制剂和异环磷酰胺引起的脑病的发生情况对患者进行比较。使用卡方检验或 Fisher 确切概率法比较定性参数，使用 Wilcoxon 检验比较定量参数。为了在分析药物制剂对异环磷酰胺引起的脑病发生的影响时纳入混杂因素，我们使用广义线性模型，将异环磷酰胺引起的脑病的发生作为因变量，制剂和混杂因素作为解释变量。
共纳入 191 例患者：103 例患者接受 HOLOXAN®（53.9%），88 例患者接受 IFOSFAMIDE EG®（46.1%）。HOLOXAN®组的中位输注时间较高（12 小时比 3 小时，P<0.001），阿瑞匹坦的使用率较高（78.6%比 69.7%，P<0.001）。11 例（5.8%，95%CI [2.9%，10.0%]）患者发生异环磷酰胺引起的脑病。在异环磷酰胺引起的脑病组中，中位输注时间较高（12 小时[12；24]比 3 小时[2；12]，P<0.001），较差的表现状态更常见（54.5%比 13.9%，P=0.002）。HOLOXAN®组异环磷酰胺引起的脑病发生率为 1.9%（2/103），IFOSFAMIDE EG®组为 10.2%（9/88）（P=0.014）。多变量分析显示，与 HOLOXAN®相比，IFOSFAMIDE EG®治疗导致异环磷酰胺引起的脑病显著增加（OR 和 95%CI：7.4 [1.4；39.5]，P=0.018）。我们还发现了另外两个异环磷酰胺引起的脑病的风险因素：长期输注和表现状态为 2 级或更高。
在 IFOSFAMIDE EG®中，溶液中氯乙胺的形成可能是导致其比 HOLOXAN®更频繁发生异环磷酰胺引起的脑病的原因。这些数据的应用可以帮助在成年患者中选择异环磷酰胺制剂，以降低异环磷酰胺引起的脑病的风险，特别是对于有风险因素的患者。
