Universität zu Köln

Queckenberg, Christian, Erlinghagen, V., Baken, B. C. M., Van Os, S. H. G., Wargenau, M., Kubes, V., Peroutka, R., Novotny, V. and Fuhr, U. (2015). Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations. Cancer Chemother. Pharmacol., 76 (5). S. 1081 - 1092. NEW YORK: SPRINGER. ISSN 1432-0843

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Abstract

To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC(0-t(last)) and C (max) were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC(0-t(last)) and C (max) (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Queckenberg, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Erlinghagen, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baken, B. C. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Os, S. H. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wargenau, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubes, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Peroutka, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Novotny, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-388590
DOI:	10.1007/s00280-015-2840-6
Journal or Publication Title:	Cancer Chemother. Pharmacol.
Volume:	76
Number:	5
Page Range:	S. 1081 - 1092
Date:	2015
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-0843
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COLORECTAL-CANCER PATIENTS; DIHYDROPYRIMIDINE DEHYDROGENASE; THYMIDYLATE SYNTHASE; BREAST-CANCER; 5-FLUOROURACIL; BIOEQUIVALENCE; CHEMOTHERAPY; POLYMORPHISM; TOXICITY; DESIGNS Multiple languages Oncology; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38859