Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer

Antonello Di Paolo, Romano Danesi, Francesca Vannozzi, Alfredo Falcone, Enrico Mini, Luca Cionini, Toni Ibrahim, Dino Amadori, Mario Del Tacca

Research output: Contribution to journalArticle

Abstract

Background: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). Methods: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m2 per day as an intravenous bolus, plus leucovorin, 100 mg/m2 per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). Results: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% ± 1.41%; percentage RMSE = 12.70% ± 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h·μg/mL) = 0.119 · C5 + 1.436 · C45 + 2.066, in which C5 and C45 are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% ± 1.37%; percentage RMSE = 12.17% ± 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% ± 0.86% and a percentage RMSE of 7.64% ± 0.81%, and the optimal sampling time points were 45 and 180 minutes. Conclusion: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.

Original languageEnglish
Pages (from-to)627-637
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume72
Issue number6
DOIs
Publication statusPublished - Dec 1 2002

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Adjuvant Chemotherapy
Fluorouracil
Colorectal Neoplasms
Pharmacokinetics
Area Under Curve
Pharmaceutical Preparations
Leucovorin
Drug Monitoring
Biotransformation
Regression Analysis
Drug Therapy
dihydrouracil
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Pharmacology

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Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer. / Di Paolo, Antonello; Danesi, Romano; Vannozzi, Francesca; Falcone, Alfredo; Mini, Enrico; Cionini, Luca; Ibrahim, Toni; Amadori, Dino; Del Tacca, Mario.

In: Clinical Pharmacology and Therapeutics, Vol. 72, No. 6, 01.12.2002, p. 627-637.

Research output: Contribution to journalArticle

Di Paolo, Antonello ; Danesi, Romano ; Vannozzi, Francesca ; Falcone, Alfredo ; Mini, Enrico ; Cionini, Luca ; Ibrahim, Toni ; Amadori, Dino ; Del Tacca, Mario. / Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer. In: Clinical Pharmacology and Therapeutics. 2002 ; Vol. 72, No. 6. pp. 627-637.
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title = "Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer",
abstract = "Background: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). Methods: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m2 per day as an intravenous bolus, plus leucovorin, 100 mg/m2 per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). Results: An optimal model based on 2 time points was obtained (percentage MPE = 1.99{\%} ± 1.41{\%}; percentage RMSE = 12.70{\%} ± 1.27{\%}), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h·μg/mL) = 0.119 · C5 + 1.436 · C45 + 2.066, in which C5 and C45 are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09{\%} ± 1.37{\%}; percentage RMSE = 12.17{\%} ± 1.23{\%}). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64{\%} ± 0.86{\%} and a percentage RMSE of 7.64{\%} ± 0.81{\%}, and the optimal sampling time points were 45 and 180 minutes. Conclusion: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.",
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T1 - Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer

AU - Di Paolo, Antonello

AU - Danesi, Romano

AU - Vannozzi, Francesca

AU - Falcone, Alfredo

AU - Mini, Enrico

AU - Cionini, Luca

AU - Ibrahim, Toni

AU - Amadori, Dino

AU - Del Tacca, Mario

PY - 2002/12/1

Y1 - 2002/12/1

N2 - Background: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). Methods: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m2 per day as an intravenous bolus, plus leucovorin, 100 mg/m2 per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). Results: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% ± 1.41%; percentage RMSE = 12.70% ± 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h·μg/mL) = 0.119 · C5 + 1.436 · C45 + 2.066, in which C5 and C45 are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% ± 1.37%; percentage RMSE = 12.17% ± 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% ± 0.86% and a percentage RMSE of 7.64% ± 0.81%, and the optimal sampling time points were 45 and 180 minutes. Conclusion: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.

AB - Background: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). Methods: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m2 per day as an intravenous bolus, plus leucovorin, 100 mg/m2 per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). Results: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% ± 1.41%; percentage RMSE = 12.70% ± 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h·μg/mL) = 0.119 · C5 + 1.436 · C45 + 2.066, in which C5 and C45 are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% ± 1.37%; percentage RMSE = 12.17% ± 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% ± 0.86% and a percentage RMSE of 7.64% ± 0.81%, and the optimal sampling time points were 45 and 180 minutes. Conclusion: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.

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