A pilot study of pharmacokinetically guided dose management of capecitabine in CRC patients.

Makihara, Katsuya; Mishima, Hideyuki; Azuma, Sayaka; Matsuyama, Kazuyo; Komori, Katsuya; Hasegawa, Hiroko; Yasui, Masayoshi; Ikenaga, Masakazu; Tsujinaka, Toshimasa

doi:10.1200/jco.2012.30.4_suppl.510

Cited by 6 publications

(4 citation statements)

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“…The My5-FU assay showed equivalent performance on different analysers such as liquid chromatography-tandem mass spectrometry (LC-MS) and other clinical analyzers 27 . A linear relationship (r = 0.9204) exists between My5-FU assays and LC-MS for plasma concentrations of capecitabine 28 . My5-FU allows for the measurement of the plasma concentration of 5-FU, which was conventionally measured using special analysis equipment as well as a general clinical laboratory instrument.…”

Section: Discussionmentioning

confidence: 91%

“…The 5-FU plasma concentration was measured at three time points: immediately, after 1.5 h and after 3 h. We measured the concentrations twice for each condition and calculated the mean value. The concentrations of 5-FU were measured by photometric detection using a homogeneous competitive nanoparticle immunoassay (My5-FU; Saladax Biomedical, Bethlehem, PA, USA) and analysed on a commercial Abbott Architect C4000 biochemical analyser as described [26][27][28][30][31][32][33] . Saladax provides a stabilizer kit as a dihydropyrimidine dehydrogenase (DPD) inhibitor.…”

Section: Measurement Of 5-fu Plasma Concentrationmentioning

confidence: 99%

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5-Nitrouracil stabilizes the plasma concentration values of 5-FU in colorectal cancer patients receiving capecitabine

Yoshida

Hashimoto

Miyazaki

et al. 2020

Sci Rep

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Capecitabine is selectively converted from 5′-DFUR to 5-fluorouracil (5-FU) in tumours by thymidine phosphorylase (TP). We investigated the addition of 5-nitrouracil (5-NU), a TP inhibitor, into blood samples for precise measurements of plasma 5-FU concentrations. The plasma concentration of 5-FU was measured after capecitabine administration. Two samples were obtained at 1 or 2 h after capecitabine administration and 5-NU was added to one of each pair. Samples were stored at room temperature or 4 °C and 5-FU concentrations were measured immediately or 1.5 or 3 h later. The mean plasma 5-FU concentration was significantly higher at room temperature than at 4 °C (p < 0.001). The 5-FU concentration was significantly increased in the absence of 5-NU than in the presence of 5-NU (p < 0.001). The 5-FU change in concentration was greater in the absence of 5-NU, and reached 190% of the maximum compared with baseline. A significant interaction was found between temperature and 5-NU conditions (p < 0.001). Differences between the presence or absence of 5-NU were greater at room temperature than under refrigerated conditions. 5-FU plasma concentrations after capecitabine administration varied with time, temperature, and the presence or absence of 5-NU. This indicates that plasma concentrations of 5-FU change dependent on storage conditions after blood collection. In current daily practice, the administrated dose of 5-fluorouracil (5-FU) is generally calculated based on the body surface area (BSA). However, BSA has been reported to be a poor predictor of systemic drug exposure 1-3. 5-FU is characterized by a narrow therapeutic window and strong exposure-toxicity relationship, which support the use of approaches to monitor drug administration. Several investigations have demonstrated a relationship between response and drug exposure in terms of toxicity and efficacy 4,5. Adjusting the 5-FU dose based on pharmacokinetic monitoring in patients led to a significantly improved response rate and fewer adverse events compared with patients treated with conventional 5-FU dose 6,7. Capecitabine, an oral drug that is tumour-selective fluoropyrimidines, is a key pro-drug of 5-FU used in colorectal cancer treatment 8. Capecitabine is primarily metabolized to 5′-deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase in the liver 9 ; 5′-DFCR is converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase, which is predominantly present in the liver as well as in tumour tissues. In the final step, 5′-DFUR is converted to its active form, 5-FU, by thymidine phosphorylase (TP), which is present at higher concentrations in cancer than in normal tissues 10. Phase I trials have demonstrated a relationship between the occurrence of adverse events and the exposure to capecitabine metabolites 11,12. Although Cmax and area under the curve (AUC) for 5′-DFUR and α-fluoro-β-alanine were found to be predictive of dose-limiting toxicities, systemic exposure to 5-FU was poorly predicted. Furthermore, Gieschke reported that the plasma concentratio...

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Section: Discussionmentioning

confidence: 91%

Section: Measurement Of 5-fu Plasma Concentrationmentioning

confidence: 99%

5-Nitrouracil stabilizes the plasma concentration values of 5-FU in colorectal cancer patients receiving capecitabine

Yoshida

Hashimoto

Miyazaki

et al. 2020

Sci Rep

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“…This resulted in the inclusion of 23 eligible studies. Nineteen clinical effectiveness studies (Additional file 3 ) [ 22 – 40 ] investigated pharmacokinetic dose adjustment, three studies [ 15 , 41 , 42 ] examined the accuracy of My5-FU assays and three studies [ 27 , 35 , 43 ] described dose adjustment algorithms of which two were also clinical effectiveness studies.…”

Section: Resultsmentioning

confidence: 99%

“…Three studies investigating accuracy against reference standard methods were included (see Additional file 4 ) [ 15 , 41 , 42 ]. In each the My5-FU assay was compared with liquid chromatography-tandem mass spectrometry (LC-MS/MS) used as the reference test.…”

Section: Resultsmentioning

confidence: 99%

Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review

et al. 2016

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BackgroundPharmacokinetic guided dosing of 5-fluorouracil chemotherapies to bring plasma 5-fluorouracil into a desired therapeutic range may lead to fewer side effects and better patient outcomes. High performance liquid chromatography and a high throughput nanoparticle immunoassay (My5-FU) have been used in conjunction with treatment algorithms to guide dosing. The objective of this study was to assess accuracy, clinical effectiveness and safety of plasma 5-fluorouracil guided dose regimen(s) versus standard regimens based on body surface area in colorectal cancer.MethodsWe undertook a systematic review. MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Library; Science Citation Index and Conference Proceedings (Web of Science); and NIHR Health Technology Assessment Programme were searched from inception to January 2014. We reviewed evidence on accuracy of My5-FU for estimating plasma 5-fluorouracil and on the clinical effectiveness of pharmacokinetic dosing compared to body surface area dosing. Estimates of individual patient data for overall survival and progression-free survival were reconstructed from published studies. Survival and adverse events data were synthesised and examined for consistency across studies.ResultsMy5-FU assays were found to be consistent with reference liquid chromatography tandem mass spectrometry. Comparative studies pointed to gains in overall survival and in progression-free survival with pharmacokinetic dosing, and were consistent across multiple studies.ConclusionsAlthough our analyses are encouraging, uncertainties remain because evidence is mainly from outmoded 5-fluorouracil regimens; a randomised controlled trial is urgently needed to investigate new dose adjustment methods in modern treatment regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2581-x) contains supplementary material, which is available to authorized users.

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PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data

2014

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PIK3CA mutations represent one of the most common genetic aberrations in breast cancer. They have been reported to be present in over one-third of cases, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes. Substantial preclinical data on the oncogenic properties of these mutations have been reported. However, whilst the preclinical data have clearly shown an association with robust activation of the pathway and resistance to common therapies used in breast cancer, the clinical data reported up to now do not support that the PIK3CA mutated genotype is associated with high levels of pathway activation or with a poor prognosis. We speculate that this may be due to the minimal use of transgenic mice models thus far. In this review, we discuss both the preclinical and clinical data associated with PIK3CA mutations and their potential implications. Prospective clinical trials stratifying by PIK3CA genotype will be necessary to determine if the mutation also predicts for increased sensitivity to agents targeting the phosphoinositide 3-kinase pathway.

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A pilot study of pharmacokinetically guided dose management of capecitabine in CRC patients.

Cited by 6 publications

References 0 publications

5-Nitrouracil stabilizes the plasma concentration values of 5-FU in colorectal cancer patients receiving capecitabine

5-Nitrouracil stabilizes the plasma concentration values of 5-FU in colorectal cancer patients receiving capecitabine

Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review

PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data

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