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

摘要

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/m(2)/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- (Circ(0)= 3.54 x 10(9)cells/mL, MTT = 204 hours and gamma = 6.0 x 10(-2)) and drug-related (slope [SLP] = 3.1 x 10(-2)mL/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 center dot 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/m(2)/24 h in monotherapy and <= 1750 and <= 600 mg/m(2)/24 h in combination with oxaliplatin, respectively, have been proposed.