Ifosfamide-induced encephalopathy: Brand-name (HOLOXAN®) vs generic formulation (IFOSFAMIDE EG®)

被引:7
作者
Chambord, Jeremy [1 ]
Henny, Fabien [1 ]
Salleron, Julia [2 ]
Hombourger, Benoit [1 ]
Lider, Pauline [3 ]
Vigneron, Jean [3 ]
Demore, Beatrice [3 ,4 ]
Vallance, Catherine [1 ]
Rios, Maria [5 ]
机构
[1] ICL, Dept Pharm, Vandoeuvre Les Nancy, France
[2] ICL, Data Biostat Unit, Vandoeuvre Les Nancy, France
[3] CHRU, Dept Pharm, Vandoeuvre Les Nancy, France
[4] Univ Lorraine, EA 4360 Apemac, Nancy, France
[5] ICL, Dept Med Oncol, Vandoeuvre Les Nancy, France
关键词
generic; ifosfamide formulation; Ifosfamide-induced encephalopathy; risk factors; RISK-FACTORS; CONTINUOUS-INFUSION; PHARMACOKINETICS; CANCER; 3-DECHLOROETHYLIFOSFAMIDE; DECHLOROETHYLATION; METABOLITES; ACID;
D O I
10.1111/jcpt.12823
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
What is known and Objective Two forms of ifosfamide are commercially available in France: HOLOXAN (R) (brand-name drug) and IFOSFAMIDE EG (R) (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 (R) or IFOSFAMIDE EG (R). Methods 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. Results and Discussion A total of 191 patients were included: 103 patients received HOLOXAN (R) (53.9%) and 88 patients received IFOSFAMIDE EG (R) (46.1%). In the HOLOXAN (R) 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 (R) 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 (R) group was 1.9% (2/103) against 10.2% (9/88) in the IFOSFAMIDE EG (R) group (P = 0.014). Multivariate analysis revealed that treatment with IFOSFAMIDE EG (R) resulted in significantly more ifosfamide-induced encephalopathies compared to HOLOXAN (R) (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. What is New and Conclusion The formation of chloroethylamine in solution could be the cause of more frequent ifosfamide-induced encephalopathies with IFOSFAMIDE EG (R) compared to HOLOXAN (R). 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.
引用
收藏
页码:372 / 380
页数:9
相关论文
共 32 条
  • [1] Agence Nationale de la Securite du medicament et des produits de sante (ANSM), 2016, REUN COM TECHN PHARM, P10
  • [2] Agence Nationale de la Securite du medicament et des produits de sante (ANSM), 2015, REUN COM TECHN PHARM, P11
  • [3] Hydroxylation and N-Dechloroethylation of Ifosfamide and Deuterated Ifosfamide by the Human Cytochrome P450s and Their Commonly Occurring Polymorphisms
    Calinski, Diane M.
    Zhang, Haoming
    Ludeman, Susan
    Dolan, M. Eileen
    Hollenberg, Paul F.
    [J]. DRUG METABOLISM AND DISPOSITION, 2015, 43 (07) : 1084 - 1090
  • [4] IFOSFAMIDE BY CONTINUOUS INFUSION TO PREVENT ENCEPHALOPATHY
    CERNY, T
    CASTIGLIONE, M
    BRUNNER, K
    KUPFER, A
    MARTINELLI, G
    LIND, M
    [J]. LANCET, 1990, 335 (8682) : 175 - 175
  • [5] Chatton JY, 2001, J PHARMACOL EXP THER, V299, P1161
  • [6] Evaluating risk factors for the development of ifosfamide encephalopathy
    David, KA
    Picus, J
    [J]. AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS, 2005, 28 (03): : 277 - 280
  • [7] Possible role of CYP2B6 genetic polymorphisms in ifosfamide-induced encephalopathy: report of three cases
    Duflot, Thomas
    Marie-Cardine, Aude
    Verstuyft, Celine
    Filhon, Bruno
    Pereira, Tony
    Massy-Guillemant, Nathalie
    Joannides, Robinson
    Bellien, Jeremy
    Lamoureux, Fabien
    [J]. FUNDAMENTAL & CLINICAL PHARMACOLOGY, 2018, 32 (03) : 337 - 342
  • [8] Ifosfamide-Induced Encephalopathy Due to a Novel Formulation of Ifosfamide
    Filhon, Bruno
    Lacarra, Boris
    Jaffray, Marie
    Hervouet, Charles
    Schneider, Pascale
    Vannier, Jean-Pierre
    [J]. PEDIATRIC BLOOD & CANCER, 2016, 63 (02) : 372 - 373
  • [9] Chemical stability and fate of the cytostatic drug ifosfamide and its N-dechloroethylated metabolites in acidic aqueous solutions
    Gilard, V
    Martino, R
    Malet-Martino, M
    Niemeyer, U
    Pohl, J
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (14) : 2542 - 2560
  • [10] GOREN MP, 1986, LANCET, V2, P1219