Abstract
Abstract Background : 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 (DOX) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. Methods: Non-Hodgkin lymphoma elderly patients were treated with a R-miniCHOP chemotherapy regimen. Dose levels were 25 mg/m², 0.7-1.4 mg/m², 750 mg/m² and 375 mg/m² for DOX, Vincristin (VCR), CP and Rituximab respectively. For PK analysis, 7 time point samples were collected over 48 h post administraion on cycle 3. CP and VIN 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 version 4.3.2). Results: 31 patients (15 males and 16 females), 75 to 96 years old, were treated with DOX and CYP. Among them, 19 patients have received VCR. A total of 134 and 120 concentrations for DOX and CP were used respectively for PK-POP modeling. A 2-compartment open model adequately described DOX concentration versus time courses. A 1-compartment open model adequately described CP concentration versus time courses. The interindividual variabilities (ISV) could be well estimated for both drugs and for all structural parameters (clearances: CL, Q, volumes of distribution: Vc, Vp) except V for CP. The population PK parameters for DOX obtained for the structural model were: CL=54.5 L/h, Q=54.7 L/h, Vc=30.6 L , Vp= 1140 L. The population PK parameters for CP were: CL=3.49 L/h, Vc=29.2 L. VCR increases DOX Vc from 30.6 L to 56.9L L/h (p =0.0012). The main covariate effects were related to gender, age, BW and to albumin. Conclusions: In this study we have estimated with very good precision PK parameters of DOX and CP in very elderly patients with DLBCL. Our data revealed the effect of gender, BW and VCR administration on DOX PK parameters. We have demonstrated the effect of increasing age on PK of CP. A PK-PD modeling will be performed in order to verify there are biological factors explaining the variation in the PK parameters of DOX and CP in elderly patients. Citation Format: Elodie BAUDRY, Anne Laure COUDREC, Pascal CHAIBI, Fanny BRET, Sara DJEBNOUN, Sophie WEILL, Samuel HUGUET, Alexandre BOYAULT, Francois LOKIEC, Keyvan REZAI. Pharmacokinetic study of RCHOP protocol in elderly patients with non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5044. doi:10.1158/1538-7445.AM2017-5044
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