A Pilot Study to Identify Sources of Variability in 5-Fluorouracil Pharmacokinetics and Toxicity
A Pilot Study to Identify Sources of Variability in 5-Fluorouracil Pharmacokinetics and Toxicity
View/Type of Scholarly Publication
DissertationDate of Exam
17.09.2007Date of Publication
2007Advisor
Fuhr, UweCo-Referee
Jaehde, UlrichMetadata
Show full item record
Citable Links 
Abstract
The aims of this study were to characterise pharmacokinetics of 5-FU and its main metabolite (5-FUH2) and to quantify factors of influence on pharmacokinetics as well as to identify factors influencing adverse events and blood cell count changes.
Thirty patients (5 females, 25 males) with colorectal or oesophageal cancer receiving 5-FU 650 or 1000 mg/m2/day as 5-day continuous infusion were entered in this study. A HPLC method was used for the simultaneous assay of 5-FU and 5-FUH2 in plasma samples obtained at baseline and at multiple time points during infusion and after the end of infusion. DPD phenotype was assessed as the UH2/U urinary concentration ratio using LC-MS/MS. Genotying assays were developed for DPYD gene (23 exons), the 5' promoter region of TYMS gene and the MTHFR gene in position 677. Population pharmacokinetics of 5-FU and 5-FUH2 were tested with NONMEM using 199 and 251 quantifiable plasma concentrations of 5-FU and 5-FUH2, respectively. Patients’ covariables were included in the modelling process after the best basic model had been identified.
An open two-compartment model with first-order elimination was found to best describe 5-FU concentration-time data, and a one-compartment model was suitable for 5-FUH2 data. The data showed that total clearance of 5-FU tends to increase with body surface area and to be higher in patients with MTHFR 677CC or 667CT genotype in the MTHFR gene. Point estimates for clearance (95% CI) were 145L/h (83-207) and 276L/h (250-302) in patients with the 667TT and the 677CT or 667CC, respectively. No relevant mutation in the DPYD, TYMS, MTHFR gene or pharmacokinetics was significantly associated with the occurrence of 5-FU adverse effect and with the changes in blood cell counts served as parameters for adverse event, respectively.
In conclusion, the present study provides pharmacokinetic data on long-term 5-FU infusion and suggest a role of the MTHFR C677T polymorphism for 5-FU clearance, which however needs to be further investigated.
Thirty patients (5 females, 25 males) with colorectal or oesophageal cancer receiving 5-FU 650 or 1000 mg/m2/day as 5-day continuous infusion were entered in this study. A HPLC method was used for the simultaneous assay of 5-FU and 5-FUH2 in plasma samples obtained at baseline and at multiple time points during infusion and after the end of infusion. DPD phenotype was assessed as the UH2/U urinary concentration ratio using LC-MS/MS. Genotying assays were developed for DPYD gene (23 exons), the 5' promoter region of TYMS gene and the MTHFR gene in position 677. Population pharmacokinetics of 5-FU and 5-FUH2 were tested with NONMEM using 199 and 251 quantifiable plasma concentrations of 5-FU and 5-FUH2, respectively. Patients’ covariables were included in the modelling process after the best basic model had been identified.
An open two-compartment model with first-order elimination was found to best describe 5-FU concentration-time data, and a one-compartment model was suitable for 5-FUH2 data. The data showed that total clearance of 5-FU tends to increase with body surface area and to be higher in patients with MTHFR 677CC or 667CT genotype in the MTHFR gene. Point estimates for clearance (95% CI) were 145L/h (83-207) and 276L/h (250-302) in patients with the 667TT and the 677CT or 667CC, respectively. No relevant mutation in the DPYD, TYMS, MTHFR gene or pharmacokinetics was significantly associated with the occurrence of 5-FU adverse effect and with the changes in blood cell counts served as parameters for adverse event, respectively.
In conclusion, the present study provides pharmacokinetic data on long-term 5-FU infusion and suggest a role of the MTHFR C677T polymorphism for 5-FU clearance, which however needs to be further investigated.
Classification (DDC)
500 Naturwissenschaften 570 Biowissenschaften, Biologie 610 Medizin, GesundheitPloylearmsaeng, Su-arpa: A Pilot Study to Identify Sources of Variability in 5-Fluorouracil Pharmacokinetics and Toxicity. - Bonn, 2007. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5N-11694
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5N-11694
@phdthesis{handle:20.500.11811/3144,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5N-11694,
author = {{Su-arpa Ploylearmsaeng}},
title = {A Pilot Study to Identify Sources of Variability in 5-Fluorouracil Pharmacokinetics and Toxicity},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2007,
note = {The aims of this study were to characterise pharmacokinetics of 5-FU and its main metabolite (5-FUH2) and to quantify factors of influence on pharmacokinetics as well as to identify factors influencing adverse events and blood cell count changes.
Thirty patients (5 females, 25 males) with colorectal or oesophageal cancer receiving 5-FU 650 or 1000 mg/m2/day as 5-day continuous infusion were entered in this study. A HPLC method was used for the simultaneous assay of 5-FU and 5-FUH2 in plasma samples obtained at baseline and at multiple time points during infusion and after the end of infusion. DPD phenotype was assessed as the UH2/U urinary concentration ratio using LC-MS/MS. Genotying assays were developed for DPYD gene (23 exons), the 5' promoter region of TYMS gene and the MTHFR gene in position 677. Population pharmacokinetics of 5-FU and 5-FUH2 were tested with NONMEM using 199 and 251 quantifiable plasma concentrations of 5-FU and 5-FUH2, respectively. Patients’ covariables were included in the modelling process after the best basic model had been identified.
An open two-compartment model with first-order elimination was found to best describe 5-FU concentration-time data, and a one-compartment model was suitable for 5-FUH2 data. The data showed that total clearance of 5-FU tends to increase with body surface area and to be higher in patients with MTHFR 677CC or 667CT genotype in the MTHFR gene. Point estimates for clearance (95% CI) were 145L/h (83-207) and 276L/h (250-302) in patients with the 667TT and the 677CT or 667CC, respectively. No relevant mutation in the DPYD, TYMS, MTHFR gene or pharmacokinetics was significantly associated with the occurrence of 5-FU adverse effect and with the changes in blood cell counts served as parameters for adverse event, respectively.
In conclusion, the present study provides pharmacokinetic data on long-term 5-FU infusion and suggest a role of the MTHFR C677T polymorphism for 5-FU clearance, which however needs to be further investigated.},
url = {https://hdl.handle.net/20.500.11811/3144}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5N-11694,
author = {{Su-arpa Ploylearmsaeng}},
title = {A Pilot Study to Identify Sources of Variability in 5-Fluorouracil Pharmacokinetics and Toxicity},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2007,
note = {The aims of this study were to characterise pharmacokinetics of 5-FU and its main metabolite (5-FUH2) and to quantify factors of influence on pharmacokinetics as well as to identify factors influencing adverse events and blood cell count changes.
Thirty patients (5 females, 25 males) with colorectal or oesophageal cancer receiving 5-FU 650 or 1000 mg/m2/day as 5-day continuous infusion were entered in this study. A HPLC method was used for the simultaneous assay of 5-FU and 5-FUH2 in plasma samples obtained at baseline and at multiple time points during infusion and after the end of infusion. DPD phenotype was assessed as the UH2/U urinary concentration ratio using LC-MS/MS. Genotying assays were developed for DPYD gene (23 exons), the 5' promoter region of TYMS gene and the MTHFR gene in position 677. Population pharmacokinetics of 5-FU and 5-FUH2 were tested with NONMEM using 199 and 251 quantifiable plasma concentrations of 5-FU and 5-FUH2, respectively. Patients’ covariables were included in the modelling process after the best basic model had been identified.
An open two-compartment model with first-order elimination was found to best describe 5-FU concentration-time data, and a one-compartment model was suitable for 5-FUH2 data. The data showed that total clearance of 5-FU tends to increase with body surface area and to be higher in patients with MTHFR 677CC or 667CT genotype in the MTHFR gene. Point estimates for clearance (95% CI) were 145L/h (83-207) and 276L/h (250-302) in patients with the 667TT and the 677CT or 667CC, respectively. No relevant mutation in the DPYD, TYMS, MTHFR gene or pharmacokinetics was significantly associated with the occurrence of 5-FU adverse effect and with the changes in blood cell counts served as parameters for adverse event, respectively.
In conclusion, the present study provides pharmacokinetic data on long-term 5-FU infusion and suggest a role of the MTHFR C677T polymorphism for 5-FU clearance, which however needs to be further investigated.},
url = {https://hdl.handle.net/20.500.11811/3144}
}
The following license files are associated with this item:
