Universität zu Köln

Arshad, Usman, Taubert, Max, Seeger-Nukpezah, Tamina, Ullah, Sami, Spindeldreier, Kirsten C., Jaehde, Ulrich, Hallek, Michael, Fuhr, Uwe, Vehreschild, Jorg Janne and Jakob, Carolin (2021). Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients. BMC Cancer, 21 (1). LONDON: BMC. ISSN 1471-2407

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Abstract

Background 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. Methods We 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. Results Plasma 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. Conclusion A 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Arshad, Usman UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, Max UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeger-Nukpezah, Tamina UNSPECIFIED UNSPECIFIED UNSPECIFIED Ullah, Sami UNSPECIFIED UNSPECIFIED UNSPECIFIED Spindeldreier, Kirsten C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaehde, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Vehreschild, Jorg Janne UNSPECIFIED UNSPECIFIED UNSPECIFIED Jakob, Carolin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-591302
DOI:	10.1186/s12885-021-08443-x
Journal or Publication Title:	BMC Cancer
Volume:	21
Number:	1
Date:	2021
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1471-2407
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACUTE LYMPHOBLASTIC-LEUKEMIA; PHARMACOKINETIC/PHARMACODYNAMIC MODEL; PEDIATRIC-PATIENTS; ADULT PATIENTS; CHILDREN; ELIMINATION; MALIGNANCIES; VARIABILITY; ADJUSTMENTS; PREDICTION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59130