Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations

Autor: S. H. G. Van Os, V. Erlinghagen, M. Wargenau, V. Kubeš, V. Novotný, B. C. M. Baken, Uwe Fuhr, Christian Queckenberg, R. Peroutka
Rok vydání: 2015
Předmět:
Adult
Male
Cancer Research
Antimetabolites
Antineoplastic
Genotype
Administration
Oral
Bioequivalence
Pharmacology
Toxicology
Deoxycytidine
Polymorphism
Single Nucleotide
Carboxylesterase
Capecitabine
Activation
Metabolic
Pharmacokinetics
Cytidine Deaminase
Dihydropyrimidine dehydrogenase
Medicine
Humans
Pharmacology (medical)
Prodrugs
Adverse effect
Alleles
Dihydrouracil Dehydrogenase (NADP)
Methylenetetrahydrofolate Reductase (NADPH2)
Aged
Thymidine Phosphorylase
biology
business.industry
Other Research Radboud Institute for Health Sciences [Radboudumc 0]
Thymidylate Synthase
Middle Aged
Neoplasm Proteins
Oncology
Liver
Therapeutic Equivalency
Fluorouracil
Methylenetetrahydrofolate reductase
Area Under Curve
biology.protein
Female
business
Floxuridine
Pharmacogenetics
medicine.drug
Tablets
Zdroj: Cancer Chemotherapy and Pharmacology, 76, 5, pp. 1081-91
Cancer Chemotherapy and Pharmacology, 76, 1081-91
ISSN: 1432-0843
0344-5704
Popis: Item does not contain fulltext PURPOSE: 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). METHODS: 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. RESULTS: 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 AUC0-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 AUC0-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). CONCLUSIONS: 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.
Databáze: OpenAIRE
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