Physiologically Based Pharmacokinetic Modeling for Prediction of 5-FU Pharmacokinetics in Cancer Patients with Hepatic Impairment After 5-FU and Capecitabine Administration.

Autor: Wang, Yu, Hu, Haihong, Yu, Lushan, Zeng, Su
Předmět:
Zdroj: Pharmaceutical Research; Sep2023, Vol. 40 Issue 9, p2177-2194, 18p
Abstrakt: Purpose: 5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment. Methods: Models including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment. Results: The PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes′ activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics. Conclusions: PBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
Externí odkaz: