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

Abstract

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.

Influence of the skeletal muscle index on pharmacokinetics and toxicity of fluorouracil

“…In general, the identified covariates on 5FU PK vary considerably. A similar influence of BSA was identified in two other published population PK models as well, 41 , 42 whereas other models revealed significant effects of sex, 36 , 43 age, 44 or body weight. 45 When applying the initial model on the new dataset, all SMI measures were positively associated with 5FU clearance when adding them as covariates and significantly improved the model fit.…”

Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans

“… 42 ). These findings collectively indicates that negative effects of 5-FU on embryonic development is closely related to its dosage, which in turn suggests that it is crucial to apply an optimal dosage that has expected anticancer activity but does not induce significant developmental defects (Refs 43 , 44 ). In this context, the mouse embryonic stem cell test seemed extremely useful to assess the developmental toxicities and determine the optimal dosage of 5-FU (Ref.…”

Fluoropyrimidine Modulation of the Anti-Tumor Immune Response―Prospects for Improved Colorectal Cancer Treatment

“…5-FU chemotherapy is immunosuppressive and a linear relationship between 5-FU plasma concentration and decreased leukocyte count was observed [ 109 ]. A recent study indicated 70% of CRC patients treated with 5-FU according to the Mayo schedule experienced ≥grade 1 hematological toxicities (neutropenia and/or leukopenia) [ 40 ].…”