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/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.

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%/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).

Conclusions: BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.

Keywords: 5-Fluorouracil; Myelosuppression; Pharmacodynamics; Pharmacogenetics; Pharmacokinetics.

Fig. 1

Schematic representation of PKPD model. Compartments with white background reflect the PK model describing 5FU and 5FUH2 plasma concentrations, while those with grey background reflect the PD model describing total WBC count over time. k_prol first order rate constant of proliferation, k_tr first-order rate constant of transit, k_circ first-order rate constant of elimination of circulating cells, Circ₀ baseline leucocyte count, γ feedback parameter, C_p 5FU plasma concentration, V_C,5FU 5FU central volume of distribution, V_P,5FU 5FU peripheral volume of distribution, CL_5FU 5FU total clearance, Q intercompartmental clearance, F_m fraction of 5FU converted to 5FUH2, V_C,5FUH2 5FUH2 central volume of distribution, CL_5FUH2 5FUH2 clearance, drug effect: E_drug = slope·C_p

Fig. 2

Visual predictive checks for 5FU (a) and 5FUH2 (b) plasma concentration data and total WBC count (c) over time. Continuous and dashed lines represent median, 2.5th and 97.5th percentiles of the observed data. Shaded areas are the 95% confidence interval for median, 2.5th and 97.5th percentiles of the simulated data. 5FU and 5FUH2 plasma concentrations are presented on a log scale

Fig. 3

Left panel; simulated total WBC count over time. Continuous line represents individuals receiving 5FU monotherapy. Dashed line represents individuals receiving combination therapy with 5FU and cisplatin. Numbers represent corresponding WBC_nadir values. Right panel: simulated total WBC over time for effects attributable to a 5FU dose as used in the FOLFIRINOX (400 mg/m² bolus 5FU followed by 2400 mg/m² over 46 h) versus the de Gramont regimens (300 mg/m² i.v. bolus followed by 300 mg/m² continuous infusion over 24 h): Continuous lines represent an individual receiving 5FU according to de Gramont regimen, while dashed lines represent an individual receiving the dose according to FOLFIRINOX regimen. Effects apply for a single treatment course, and those of the other components of the respective regimens are ignored in this figure. Numbers represent corresponding WBC_nadir values