Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations
Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations
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重复服用两种 500 mg 片剂后卡培他滨及其代谢物的药代动力学和药物遗传学
DOI：
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发表时间：
2015
影响因子：
3
通讯作者：
U. Fuhr
中科院分区：
文献类型：
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作者：
Christian Queckenberg;V. Erlinghagen;B. C. M. Baken;S. H. G. Van Os;M. Wargenau;V. Kubeš;R. Peroutka;V. Novotny;U. Fuhr
目的描述卡培他滨及其代谢产物5′-DFUR、5′-DFCR和5-FU的浓度-时间曲线，这取决于片剂剂型和胞苷脱氨酶、二氢嘧啶脱氢酶、胸苷酸合成酶和亚甲基四氢叶酸还原酶（MTHFR）的常见和/或相关遗传多态性。在连续四个早晨用研究药物代替个体治疗剂量。以随机分配的序列TRTR或RTRT（重复设计）给予适当数量的500 mg试验（T）或参比（R）卡培他滨片剂。平均生物利用度进行了评估ANOVA.Results30名女性和16名男性患者患有胃肠道或乳腺癌（平均年龄53.4岁，平均剂量1739毫克）。AUC 0-t（last）和Cmax的T/R比分别为96.7%（98%CI 90.7- 103.2%）和87.2%（98%CI 74.9- 101.5%）。AUC 0-t（last）和Cmax（R的变异系数）的受试者内变异性分别为16.5%和30.2%。所有代谢产物的结果相似。未发生严重不良事件。对于MTHFR C677 T（rs 1801133）基因型，677 C等位基因数量的增加与卡培他滨消除半衰期的增加呈临界相关（p = 0.043）。虽然认为这些差异不具有临床相关性，但缺少正式的生物等效性标准。MTHFR基因型在卡培他滨和/或5-FU药代动力学中可能的间接作用应在进一步的研究中进行研究。
PurposeTo describe concentration versus time profiles of capecitabine and its metabolites 5′-DFUR, 5′-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR).MethodsIn 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA.ResultsThirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0–t(last) and Cmax were 96.7 % (98 % CI 90.7–103.2 %) and 87.2 % (98 % CI 74.9–101.5 %), respectively. Within-subject variability for AUC0–t(last) and Cmax (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043).ConclusionsThe extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.