Abstract
PurposeTo describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach.MethodsThirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m2/day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m2/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 semi-mechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics.ResultsTotal 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%/m2 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 × 109/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).ConclusionsBSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.
Highlights
The pyrimidine antimetabolite 5-fluorouracil (5FU) is being used since decades for the treatment of gastrointestinal solid malignancies [1]
Investigations have been carried out evaluating patient’s factors to predict 5FU exposure, where a relationship between body surface area (BSA) and 5FU clearance (CL5FU) was reported [3, 5]. CL5FU was found to be lower in females [6] and at older age [5, 7]
white blood cell (WBC) count was evaluated once prior to and 1–3 times per week after 5FU administration, but prior to the second cycle starting on day 28, as the assessment of myelosuppression was aimed to be investigated under the influence of single cycle of treatment
Summary
The pyrimidine antimetabolite 5-fluorouracil (5FU) is being used since decades for the treatment of gastrointestinal solid malignancies [1]. Route and schedule of administration have been identified to influence 5FU pharmacokinetics (PK) and effects [2, 3]. Considerable variations in PK and toxicity are associated with a given 5FU dosing regimen [4]. Investigations have been carried out evaluating patient’s factors to predict 5FU exposure, where a relationship between body surface area (BSA) and 5FU clearance (CL5FU) was reported [3, 5]. Elimination of the drug was reported to be influenced by hepatic metastases [3] and by glomerular filtration rate as measured by creatinine clearance [6]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
