Population pharmacokinetic analysis of 5-FU and 5-FDHU in colorectal cancer patients: search for biomarkers associated with gastro-intestinal toxicity.

Abstract

PURPOSE:

The anticancer drug 5-fluorouracile (5-FU) which is indicated for the treatment of a variety of solid malignancies such as colorectal, breast, head and neck neoplasms is extensively biotransformed to 5 fluoro-5,6- dihydrouracil (5-FDHU) by the dihydropyrimidine deshydrogenase enzyme (DPD). DPD deficiency is recognized as an important risk factor, predisposing patient to undergo severe/lethal toxicities. To date, relationships between 5-FU, 5- FDHU and toxicity following i.v. bolus administration has not been studied using the population pharmacokinetics approach.

METHODS:

Retrospective pharmacokinetic data of 5-FU and 5-FDHU from 127 colorectal cancer patients were used for the population pharmacokinetic analysis. Treatment schedule consisted of an adjuvant therapy with 5-FU plus leucovorin. 5- FU and 5-FDHU complete plasma profiles recorded on day-1 of the first chemotherapy cycle were modeled simultaneously using NONMEM software. Gastro-intestinal adverse events graded according to the WHO criteria were recorded after the first cycle. A population logistic regression model was developed to identify predictive factors of these adverse events.

RESULTS:

A three-compartment pharmacokinetic mixture model best described 5-FU and 5-FDHU kinetics profiles. Linear and saturated elimination from the central compartment of 5-FU and a linear elimination from the 5-FDHU compartment were used. A bimodal distribution of the inter-compartmental clearance was observed allowing two subpopulation with high (17 L/h) and low values (3.35 L/h). DPD-phenotype is suspected to explain this mixture. No covariates were introduced in the final model. Also, no relationship was found between maximal metabolism rate and DPD-phenotype. Predictive factors associated with occurrence of high grade gastro-intestinal adverse events were gender, dose and lean body mass suggesting serious cautions with the BSA-weighted dose for women. For the low-grade toxicities, 5-FU area under curve was predictive for woman and 5-FDHU area under curve for men.

CONCLUSION:

A population pharmacokinetic mixture model was developed to describe kinetic profiles of 5-FU and its major metabolite. This model has significant implications, to identify patients with potentially low DPD phenotype requiring earlier adjustment of the 5-FU dose. Also this analysis highlights the need for developing alternative dosing-scheme for women.

• Authors: Christian Woloch, Antonello Di Paolo, Hafedh Marouani, Guido Bocci, Joseph Ciccolini, Bruno Lacarelle, Romano Danesi, Athanassios Iliadis
• Journal: Current topics in medicinal chemistry (Curr Top Med Chem) Vol. 12 Issue 15 Pg. 1713-9 ( 2012) ISSN: 1873-4294 [Electronic] United Arab Emirates
• PMID: 22978343 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• 5-fluorodihydrouracil
• Fluorouracil

Topics

• Aged
• Biomarkers (analysis)
• Chemotherapy, Adjuvant
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Diarrhea (chemically induced)
• Female
• Fluorouracil (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Humans
• Logistic Models
• Male
• Middle Aged
• Models, Biological
• Nausea (chemically induced)
• Retrospective Studies
• Vomiting (chemically induced)