Universität zu Köln

Arshad, Usman ORCID: 0000-0002-7003-5300, Ploylearmsaeng, Su-arpa, Karlsson, Mats O., Doroshyenko, Oxana, Langer, Dorothee, Schoemig, Edgar, Kunze, Sabine, Guener, Semih A., Skripnichenko, Roman, Ullah, Sami, Jaehde, Ulrich, Fuhr, Uwe, Jetter, Alexander and Taubert, Max ORCID: 0000-0001-8925-7782 (2020). Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic-pharmacodynamic model in gastrointestinal cancer patients. Cancer Chemother. Pharmacol., 85 (4). S. 711 - 723. NEW YORK: SPRINGER. ISSN 1432-0843

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Abstract

Purpose To describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach. Methods Thirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m(2)/day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m(2)/day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semi-mechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics. Results Total clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m(2) difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 x 10(9)/L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg). Conclusions BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Arshad, Usman UNSPECIFIED orcid.org/0000-0002-7003-5300 UNSPECIFIED Ploylearmsaeng, Su-arpa UNSPECIFIED UNSPECIFIED UNSPECIFIED Karlsson, Mats O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Doroshyenko, Oxana UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Dorothee UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoemig, Edgar UNSPECIFIED UNSPECIFIED UNSPECIFIED Kunze, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Guener, Semih A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Skripnichenko, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Ullah, Sami UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaehde, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Jetter, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, Max UNSPECIFIED orcid.org/0000-0001-8925-7782 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-339152
DOI:	10.1007/s00280-019-04028-5
Journal or Publication Title:	Cancer Chemother. Pharmacol.
Volume:	85
Number:	4
Page Range:	S. 711 - 723
Date:	2020
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-0843
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADVANCED COLORECTAL-CANCER; DIHYDROPYRIMIDINE DEHYDROGENASE; GENE POLYMORPHISMS; PHASE-III; FLUOROURACIL; TOXICITY; CHEMOTHERAPY; CISPLATIN; REGIMEN; 5-FU Multiple languages Oncology; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33915