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- Title
Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic-pharmacodynamic model in gastrointestinal cancer patients.
- Authors
Arshad, Usman; Ploylearmsaeng, Su-arpa; Karlsson, Mats O.; Doroshyenko, Oxana; Langer, Dorothee; Schömig, Edgar; Kunze, Sabine; Güner, Semih A.; Skripnichenko, Roman; Ullah, Sami; Jaehde, Ulrich; Fuhr, Uwe; Jetter, Alexander; Taubert, Max
- Abstract
<bold>Purpose: </bold>To describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach.<bold>Methods: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.
- Subjects
GASTROINTESTINAL cancer; PHARMACOKINETICS; FORECASTING; PHARMACODYNAMICS; MYELOSUPPRESSION; LEUKOCYTE count; BODY surface area
- Publication
Cancer Chemotherapy & Pharmacology, 2020, Vol 85, Issue 4, p711
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-019-04028-5