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

Autor: Sáez-Belló M, Mangas-Sanjuán V, Martínez-Gómez MA, López-Montenegro Soria MÁ, Climente-Martí M, Merino-Sanjuán M
Rok vydání: 2021
Předmět:
Zdroj: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
r-FISABIO: Repositorio Institucional de Producción Científica
Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
r-FISABIO. Repositorio Institucional de Producción Científica
instname
ISSN: 0306-5251
Popis: 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
Databáze: OpenAIRE
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