No effect of dose, hepatic function, or nutritional status on 5-FU clearance following continuous (5-day), 5-FU infusion

Fleming, Ronald A.; Milano, Gérard; Etienne, Marie‐Christine; Renée, Nicole; Thyss, Antoine; Schneider, M.; Démard, F

doi:10.1038/bjc.1992.335

Cited by 37 publications

(8 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CL 5FU of 249 L/h was comparable to the estimates obtained in similarly designed studies. Non-compartmental analysis with a 5-day continuous infusion estimated the CL 5FU to be 257 L/h [42], while an estimate of 270 L/h was reported for a 3-day continuous infusion [43]. Population pharmacokinetic analysis performed by Etienne et al presented an estimate of 235 L/h, where the data were described by a one-compartment model with first-order elimination [7].…”

Section: Discussionmentioning

confidence: 99%

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

Arshad

Ploylearmsaeng

Karlsson

et al. 2020

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Purpose To describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach. Methods Thirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m 2 /day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m 2 /day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semimechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics. Results Total clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m 2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 10 9 /L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg). Conclusions BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.

show abstract

Section: Discussionmentioning

confidence: 99%

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

Arshad

Ploylearmsaeng

Karlsson

et al. 2020

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

show abstract

“…25 Likewise, as our study reflects, other authors did not found a significant influence of hepatic function tests on predicting 5-FU Cl. 27 Plasma clearance of 5-FU is rate limited on the catabolic pathway by the activity of the dihydropyrimidine dehydrogenase (DPD). 28 It is now well recognized that decrease DPD enzyme activity can predispose cancer patients to severe life-threatening toxicity following treatment with routine doses of 5-FU.…”

Section: Discussionmentioning

confidence: 99%

A Bayesian Method for Predicting 5‐Fluorouracil Pharmacokinetic Parameters Following Short‐Term Infusion in Patients With Colorectal Cancer

Climente‐Martí

Merino-Sanjuán

Almenar-Cubells

et al. 2003

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

“…5-FU clearance is highly variable and several factors contributing to its variability have been reported. Polymorphism in the gene coding for DPD (DPYD) has already been addressed and has been extensively discussed elsewhere [5,25] but age, gender, disease state and organ dysfunction (particularly liver failure) have also been reported to have an impact on 5-FU pharmacokinetics [26] [27,28]. Absence of correlation between body surface area and 5-FU clearance has been extensively demonstrated [29], [13].…”

Section: Metabolism and Excretion: (Figure 1)mentioning

confidence: 99%

How can we best monitor 5-FU administration to maximize benefit to risk ratio?

Goirand

Lemaître

Launay

et al. 2018

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

Introduction: 5-FU is currently used as a chemotherapy in several cancers such as head-andneck (H&N) and colorectal cancers (CRC). 5-FU dosing is traditionally based on bodysurface-area, but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM). Areas covered: 5-FU Pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed. Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under-or over-exposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers.

show abstract

No effect of dose, hepatic function, or nutritional status on 5-FU clearance following continuous (5-day), 5-FU infusion

Cited by 37 publications

References 17 publications

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

A Bayesian Method for Predicting 5‐Fluorouracil Pharmacokinetic Parameters Following Short‐Term Infusion in Patients With Colorectal Cancer

How can we best monitor 5-FU administration to maximize benefit to risk ratio?

Contact Info

Product

Resources

About