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

Sami Ullah,Ulrich Jaehde,Carolin Jakob,Tamina Seeger-Nukpezah,Usman Arshad,Jörg Janne Vehreschild,Uwe Fuhr,Max Taubert,Kirsten C Spindeldreier,Michael Hallek

doi:10.1186/s12885-021-08443-x

Abstract

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.

Highlights

Methotrexate (MTX) is considered an efficacious, costeffective and acceptably safe drug for the treatment of many hematological/oncological disorders and autoimmune diseases [1]
To handle the variability associated with MTX exposure, monitoring of its plasma concentrations and serum creatinine (SCr) is recommended to safeguard a relatively constant drug exposure with an acceptable risk/benefit ratio in patients with impaired renal function [12]
MTX dosing is often guided by body surface area (BSA) estimates to account for body size-related differences in CL and volume of distribution (V)

Summary

Introduction

Methotrexate (MTX) is considered an efficacious, costeffective and acceptably safe drug for the treatment of many hematological/oncological disorders and autoimmune diseases [1]. To handle the variability associated with MTX exposure, monitoring of its plasma concentrations (therapeutic drug monitoring, TDM) and serum creatinine (SCr) is recommended to safeguard a relatively constant drug exposure with an acceptable risk/benefit ratio in patients with impaired renal function [12]. MTX dosing is often guided by body surface area (BSA) estimates to account for body size-related differences in CL and volume of distribution (V). The 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

Objectives

Methods

Results