Unité de Geriatrie Aigüe CHU Bicêtre, 78 Rue du Général Leclerc, 94270, Le Kremlin-Bicêtre, France.
Radio-Pharmacology Department, Institut Curie, 35 Rue Dailly, 92210, Saint Cloud, France.
Cancer Chemother Pharmacol. 2019 Apr;83(4):775-785. doi: 10.1007/s00280-019-03775-9. Epub 2019 Jan 28.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs.
This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m, 0.7-1.4 mg/m, 750 mg/m, and 375 mg/m for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix).
31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded.
Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.
弥漫性大 B 细胞淋巴瘤（DLBCL）是老年患者中最常见的淋巴瘤，R-CHOP 化疗是 DLBCL 的标准治疗方案。老年患者（通常定义为 75 岁）使用抗癌药物时需要谨慎；然而，这些药物在该人群中的药代动力学和药效学（PK 和 PD）尚未得到彻底研究。在这项研究中，我们研究了老年患者中环磷酰胺（CP）和多柔比星（DOXO）的 PK，以验证年龄是否会影响这些抗癌药物的 PK。
这是一项前瞻性多中心临床试验，研究了接受 R-mini-CHOP 方案治疗的 DLBCL 老年和非常老年患者中 CP 和 DOXO 的 PK。剂量水平分别为 DOXO、长春新碱（VCR）、CP 和利妥昔单抗的 25mg/m、0.7-1.4mg/m、750mg/m 和 375mg/m。对于 PK 分析，在第 3 周期给药后 48 小时内采集了 7 个时间点的样本。使用 UPLC-MS/MS 验证方法测量 CP 和 VCR 的血浆浓度。使用 UPLC 结合荧光检测验证方法测量 DOX 血浆浓度。使用非线性混合效应模型程序（Monolix）进行 PK-POP 建模。
31 名患者（15 名男性和 16 名女性），年龄 75 至 96 岁，接受了 R-miniCHOP 方案治疗。其中 19 名患者接受了 VCR 治疗。CP 浓度-时间曲线的单室（1cpt）开放模型以线性消除方式得到了很好的描述。CP 的群体 PK 参数为：CL = 3.58 L/h，Vmale = 32.2 L，Vfemale = 28.7 L。体重（BW）、白蛋白血症和性别对 CP PK 有显著影响。线性消除的 2 室（2cpt）开放模型最能描述 DOXO 的浓度-时间曲线。结构模型中获得的 DOXO 的群体 PK 参数为：CL = 51.1 L/h，Q = 49.6 L/h，V1 = 29.4 L，V2 = 1,130 L（清除率：CL、Q，分布体积：V1、V2）。DOXO PK 的主要协变量影响与性别、BW 和 VCR 给药有关。VCR 使 DOXO 的 V1 从 29.4 L 增加到 57.5 L（p = 0.02）。未记录到 3 级或 4 级血液学和心脏毒性。
通常情况下，在缺乏具体数据的情况下，大多数医生会根据经验减少老年患者的抗癌药物剂量（Tourani 在 J Geriatr Oncol 3(1): 41-48, 2012），甚至不治疗这些非常老年患者。更好地了解老年患者的药代动力学，应允许根据最显著的生理因素来更好地调整基于 PK 参数的剂量。在这项研究中，这些非常老年患者（84.1 岁）没有观察到严重的毒性。这表明，化疗药物的剂量调整不应仅基于年龄和肌酐清除率，还应基于适当的生理和生物学数据。我们的研究结果表明，CP 剂量调整应根据血清白蛋白水平以及患者的 BW 和性别进行。
