Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

BMC Cancer

Tamina Seeger-Nukpezah¹  Carolin Jakob¹  Michael Hallek¹  Jörg Janne Vehreschild²  Uwe Fuhr³  Max Taubert³  Sami Ullah⁴  Usman Arshad⁴  Kirsten C. Spindeldreier⁵  Ulrich Jaehde⁶ 

[1] Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany;Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany;German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany;Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine and University Hospital of Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany;Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany;Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany;Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany;Hospital Pharmacy, University Hospital Cologne, Cologne, Germany;Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany;

关键词: Methotrexate;    Pharmacokinetics;    Covariates;    Dosing;   

DOI  :  10.1186/s12885-021-08443-x

来源: Springer

【 摘 要 】

BackgroundThe aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies.MethodsWe conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens.ResultsPlasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall.ConclusionA dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

【 授权许可】

CC BY