Influence of capecitabine absorption on its metabolites pharmacokinetics: a bioequivalence study

卡培他滨 医学 生物等效性 最大值 药代动力学 药理学 内科学 结直肠癌 肿瘤科 癌症
作者
L. Chaigneau,Bernard Royer,Damien Montange,Tri‐Hung Nguyen,Tristan Maurina,Cristian Villanueva,Martin Demarchi,Christophe Borg,C. Fagnoni-Legat,Jean Pierre Kantelip,Xavier Pivot
出处
期刊:Annals of Oncology [Elsevier BV]
卷期号:19 (11): 1980-1981 被引量:11
标识
DOI:10.1093/annonc/mdn662
摘要

The clinical interest of capecitabine (Xeloda ®, Roche) administration lies in the areas of safety, quality of live, oral administration and shorter duration of hospitalisation [1.Chong G. Cunningham D. Can cisplatin and infused 5-fluorouracil be replaced by oxaliplatin and capecitabine in the treatment of advanced oesophagogastric cancer? The REAL 2 trial.Clin Oncol (R Coll Radiol). 2005; 17: 79-80Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 2.Gelmon K. Chan A. Harbeck N. The role of capecitabine in first-line treatment for patients with metastatic breast cancer.Oncologist. 2006; 11: 42-51Crossref PubMed Scopus (38) Google Scholar]. However, patients unable to swallow the tablets cannot benefit of this oral prodrug. To tackle this issue, we studied bioequivalence between crushed tablets and plain capecitabine tablets. Fourteen cancer patients were included in two arms of a randomised, single-centre intrapatient crossover phase I trial: regular commercial tablets on day 1 (1250 mg/m2 b.i.d.), then crushed regular commercial tablets on day 2 in the first arm and the opposite in the other arm. The administration of crushed tablets was carried out after dispersion in 40 ml of water. Eight pharmacokinetic samples were taken each morning during 6 h. Measurement of capecitabine and metabolites [5′-DFCR (5′-deoxy-5-fluorocytidine), 5′-DFUR (5′-deoxy-5-fluorouridine) and 5-fluorouracil (5-FU)] was carried out by HPLC with UV detection. Exposition was (AUC0–6) calculated by trapezoidal method, maximal concentration (Cmax), time to Cmax (Tmax) and apparent elimination constant (ke). Bioequivalence is defined as the relative 90% confidence interval (CI90) between 80% and 125% of the geometric mean as compared with the reference formulation [3.Centre for Drug Evaluation and Research - Food and Drug Administration. Bioavailability and bioequivalence studies for orally administered drug products—General considerations [online] March 2003; http://www.fda.gov/cder/guidance/5356fnl.pdf (11 June 2008, date last accessed)Google Scholar]. A two-way analysis of variance with ‘sequence’, ‘period’, ‘treatment’ and ‘patients in treatment effects was applied to estimate the residual variance used for the calculation of CI90, whereas ke, and Tmax were compared using paired nonparametric comparisons (Wilcoxon test). High interindividual variability was observed with all compounds independent of the given galenic formulations (Figure 1). The administration of the crushed tablets resulted in statistically faster and more extensive absorption without modification of elimination process (ke) for all molecules. Interestingly, the study of individual pharmacokinetic profiles showed that the profiles of the metabolites, including 5-FU, followed that of capecitabine, indicating that its absorption is of great importance for the production and kinetics of these metabolites. Together with the variability of enzymes implied in 5-FU metabolism (thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase), this variability might suggest the potential need to perform therapeutic drug monitoring (TDM) in patients treated by capecitabine. For all compounds, bioequivalence was observed for area under the curve (AUC), but not for Cmax. For instance, the ratio between the AUC and the Cmax of the two formulations was, respectively, 101.1% (88.0% to 116.2) and 153.6% (1.093–2.159) for capecitabine and 94.6% (82.8% to 108.2) and 164.3% (119.1% to 226.7%) for 5-FU. The crushing of the regular tablets induced a faster and a more extensive absorption of capecitabine and, as previously mentioned, all metabolite pharmacokinetics are influenced by this absorption (Figure 1). Nevertheless, the AUC0–6 remained comparable and bioequivalence could be reached for this major parameter. We thus think that capecitabine crushed tablet-based treatments could be administered without dose adaptation allowing an extension of the use of capecitabine. Indeed, AUC is the main parameter used to assess and monitor toxicity, tumour response or survival [4.Ploylearmsaeng S.A. Fuhr U. Jetter A. How may anticancer chemotherapy with fluorouracil be individualised?.Clin Pharmacokinet. 2006; 45: 567-592Crossref PubMed Scopus (43) Google Scholar]. Administration of crushed tablets of capecitabine can be suitable for patients unable to swallow tablets. Attention should be nevertheless paid regarding the potential need for TDM due to the high impact of capecitabine absorption on the pharmacokinetics of metabolites. Ligue contre le cancer, comité du Doubs .
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
黄海完成签到,获得积分20
1秒前
1秒前
2秒前
2秒前
4秒前
某某完成签到,获得积分10
4秒前
congenialboy发布了新的文献求助10
6秒前
孙燕应助ioio采纳,获得20
7秒前
Della发布了新的文献求助10
7秒前
Everything完成签到,获得积分10
8秒前
黄海发布了新的文献求助10
8秒前
9秒前
10秒前
10秒前
幸福大白发布了新的文献求助10
11秒前
11秒前
c2完成签到,获得积分10
11秒前
Hey发布了新的文献求助20
11秒前
11秒前
11秒前
科研力力完成签到 ,获得积分10
11秒前
12秒前
13秒前
13秒前
13秒前
幸福大白发布了新的文献求助10
13秒前
13秒前
c2发布了新的文献求助10
14秒前
lalala发布了新的文献求助10
14秒前
15秒前
殷勤的哈密瓜完成签到,获得积分10
15秒前
16秒前
阜睿发布了新的文献求助10
17秒前
紫竹魔笛发布了新的文献求助10
17秒前
高兴芯发布了新的文献求助10
18秒前
18秒前
展希希发布了新的文献求助10
19秒前
20秒前
李健应助liii采纳,获得10
20秒前
辛辛完成签到,获得积分10
22秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989510
求助须知:如何正确求助?哪些是违规求助? 3531756
关于积分的说明 11254536
捐赠科研通 3270255
什么是DOI,文献DOI怎么找? 1804947
邀请新用户注册赠送积分活动 882113
科研通“疑难数据库(出版商)”最低求助积分说明 809176