Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients
| Autor: | Usman Arshad, Alexander Jetter, Sami Ullah, Su-arpa Ploylearmsaeng, Semih A. Güner, Uwe Fuhr, Edgar Schömig, Ulrich Jaehde, Mats O. Karlsson, Max Taubert, Sabine Kunze, Oxana Doroshyenko, Dorothee Langer, Roman Skripnichenko |
|---|---|
| Přispěvatelé: | University of Zurich, Arshad, Usman |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research Continuous infusion Myelosuppression Pharmacology Toxicology Pharmaceutical Sciences 2736 Pharmacology (medical) 1306 Cancer Research Pharmacology (medical) Myeloid Cells Tissue Distribution Pharmaceutical sciences Infusions Intravenous Gastrointestinal Neoplasms Pharmacokinetic pharmacodynamic 3005 Toxicology Middle Aged Prognosis 3004 Pharmacology Oncology Fluorouracil 2730 Oncology Original Article Female medicine.drug Adult Antimetabolites Antineoplastic 5-Fluorouracil 610 Medicine & health Models Biological Pharmacokinetics medicine Humans Gastrointestinal cancer Aged business.industry Farmaceutiska vetenskaper medicine.disease Pharmacodynamics Nonlinear Dynamics 10199 Clinic for Clinical Pharmacology and Toxicology Pharmacogenetics business Follow-Up Studies |
| Zdroj: | Cancer Chemotherapy and Pharmacology |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink