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RESEARCH PRODUCT

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

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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 × 10-2 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·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.