Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis
Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis
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DOI：
10.1002/psp4.12474
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发表时间：
2019-11-20
影响因子：
3.5
通讯作者：
Huitema, Alwin D. R.
中科院分区：
文献类型：
--
作者：
Jacobs, Bart A. W.;Deenen, Maarten J.;Huitema, Alwin D. R.
卡培他滨是抗癌药物5-氟尿嘧啶（5-FU）的口服前药。本研究的主要目的是使用来自参与七项临床研究的异质性癌症患者群体（n = 237）的数据，开发卡培他滨及其代谢物5 '-脱氧-5-氟胞苷（dFCR）、5 '-脱氧-5-氟尿苷（dFUR）、5-FU和氟代-β-丙氨酸（FBAL）的药代动力学模型。四转运模型充分描述了卡培他滨的吸收。卡培他滨、dFCR和FBAL的药代动力学可用二室模型描述，dFUR和5-FU的药代动力学受触发器影响。部分和全胃切除术与卡培他滨吸收显著加快相关，导致卡培他滨和代谢物峰浓度升高。对于编码二氢嘧啶脱氢酶的基因突变（DPYD*2A突变）为杂合子多态性的患者，5-FU消除减少21.5%（相对标准误差11.2%）。该综合人群模型广泛概述了卡培他滨及其代谢产物在大量异质性癌症患者人群中的药代动力学。
Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5 '-deoxy-5-fluorocytidine (dFCR), 5 '-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-beta-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients.