Evaluation of ABC gene polymorphisms on the pharmacokinetics and pharmacodynamics of capecitabine in colorectal patients: Implications for dosing recommendations

Abstract

Aims The aims are to develop a population pharmacokinetic model of capecitabine (CAP) and its main metabolites after the oral administration of CAP in colorectal cancer patients with different polymorphisms of the ATP‐binding cassette (ABC) gene and a population pharmacokinetic/pharmacodynamic model capable of accounting for the neutropenic effects, and to optimize the dosing strategy based on the polymorphisms of the ABC gene and/or the administration regimen as a single agent or in combination. Methods Forty‐eight patients diagnosed with colorectal cancer were included, with 432 plasma levels of CAP, 5′‐desoxi‐5‐fluorouridine (5′‐DFUR) and 5‐fluorouracil (5‐FU), and 370 neutrophil observations. Capecitabine doses ranged from 1250 to 2500 mg/m2/24 h. Plasma measurements of CAP, 5′‐DFUR and 5‐FU were obtained at 1, 2 and 3 hours post administration. Neutrophil levels were measured between day 15 and day 24 post administration. Results The pharmacokinetic model incorporates oxaliplatin as a covariate on absorption lag time, rs6720173 (ABCG5 gene) on clearance of 5′‐DFUR (182% increase for mutated rs6720173) and rs2271862 (ABCA2 gene) on clearance of 5‐FU (184% increase for mutated rs2271862). System‐ (Circ0 = 3.54 × 109 cells/mL, MTT = 204 hours and γ = 6.0 × 10−2) and drug‐related (slope [SLP] = 3.1 × 10−2mL/mg). Co‐administration of oxaliplatin resulted in a 2.84‐fold increase in SLP. The predicted exposure thresholds to G3/4 neutropenia in combination and monotherapy were 26 and 70 mg·h/L, respectively. Conclusions The population pharmacokinetic/pharmacodynamic model characterized the time course of capecitabine and its metabolites in plasma. Dose recommendations of capecitabine in patients with mutated and wild allele for single nucleotide polymorphisms rs2271862 of ≤3000 and ≤2400 mg/m2/24 h in monotherapy and ≤1750 and ≤600 mg/m2/24 h in combination with oxaliplatin, respectively, have been proposed.

Application of Pharmacometrics of 5-Fluorouracil to Personalized Medicine: A Tool for Predicting Pharmacokinetic–Pharmacodynamic/Toxicodynamic Responses

“…Although TDM of 5-FU can reduce toxicity and improve clinical efficacy in long-term infusion regimens, a TDM strategy has not yet been established for 5-FU prodrugs. To elucidate the relationship between exposure to the drug and its toxic properties, some studies performed PK-TD model analysis of 5-FU prodrugs (51,57). Recently, Oyaga-Iriarte et al successfully developed a multicompartmental PK model for capecitabine and its metabolite in patients and determined optimal sampling times for capecitabine during TDM procedures (62).…”

Medicamenta ad sentinam, et defectum vitae: Drugs and failure of the pump of life‐cardiotoxicity of oncotherapeutics

“…This is potentially why patients with pre‐existing cardiac ischaemia are particularly prone to 5‐FU cardiomyocyte toxicity. In addition, further evaluation of polymorphisms in the drug transporter ATP binding cassette (ABC) genes, which are associated with capecitabine toxicity, 8 could be biomarkers for its cardiotoxicity. The hypothesized mechanisms causing this 5‐FU adverse effect are that the parent pyrimidine analogue and its metabolites inhibit endothelial nitric oxide synthase with its attendant down‐stream effects on endothelin 1 upregulation and protein kinase C, combined with enhanced generation of reactive oxygen species producing DNA and other macromolecular damage 1 …”