Impact of capecitabine and S-1 on anticoagulant activity of warfarin in patients with gastrointestinal cancer

Hata, Tsuyoshi; Kudo, Toshihiro; Sakai, Daisuke; Takahashi, Hidekazu; Haraguchi, Naotsugu; Nishimura, Junichi; Hata, Taishi; Mizushima, Tsunekazu; Yamamoto, Hirofumi; Doki, Yuichiro; Mori, Masaki; Satoh, Taroh

doi:10.1007/s00280-016-3080-0

Cited by 5 publications

(8 citation statements)

References 30 publications

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“…There have been numerous reports suggesting a drug‐drug interaction (DDI) between fluoropyrimidines and warfarin, an anticoagulant with a narrow therapeutic index widely used for prevention and treatment of thrombosis and embolism . Altered coagulation parameters and/or bleeding have been observed within several days and up to several months after initiation of capecitabine therapy in patients with concomitant warfarin, and up to 1 month after stopping capecitabine .…”

mentioning

confidence: 99%

“…1 The drug is approved for first-line treatment of patients with metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred, for adjuvant treatment of colon cancer after primary tumor resection, and for treatment of metastatic breast cancer. 2 There have been numerous reports suggesting a drug-drug interaction (DDI) between fluoropyrimidines and warfarin, [3][4][5][6][7][8][9][10][11] an anticoagulant with a narrow therapeutic index widely used for prevention and treatment of thrombosis and embolism. 12 Altered coagulation parameters and/or bleeding have been observed within several days and up to several months after initiation of capecitabine therapy in patients with concomitant warfarin, and up to 1 month after stopping capecitabine.…”

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confidence: 99%

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Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

Ramı́rez

House

Karrison

et al. 2019

The Journal of Clinical Pharma

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This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug‐drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals (CIs) of the drug exposure ratios fall within the range of 0.80 to 1.25. Comparison of steady‐state pharmacokinetic parameters of celecoxib between day 7 (cycle 0, celecoxib only) and day 14 (cycle 1, celecoxib + capecitabine) showed geometric mean ratios of 1.24 (90%CI, 1.04‐1.49), 1.30 (1.11‐1.53) and 1.28 (1.11‐1.47) for maximum plasma concentration, minimum plasma concentration, and area under the concentration‐time curve from time zero to 8 hours, respectively. Comparison of day 7 vs day 21 (cycle 1, after 1 week washout of capecitabine) showed a further increase in the geometric mean ratio of maximum plasma concentration (1.39; 90%CI, 1.16‐1.66), minimum plasma concentration (1.53; 1.10‐2.12) and area under the concentration‐time curve from time zero to 8 hours (1.41; 1.19‐1.68). Because the 90%CIs fell outside the prespecified equivalence margin, we conclude that coadministration results in a DDI (increased celecoxib exposure) that persists for at least 7 days after capecitabine discontinuation. Close monitoring should be undertaken when administering fluoropyrimidines with CYP2C9 substrates with narrow therapeutic indexes while also weighing the benefits and risks for individual patients.

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confidence: 99%

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confidence: 99%

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

Ramı́rez

House

Karrison

et al. 2019

The Journal of Clinical Pharma

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“…[1][2][3] WF consists of a racemic mixture of S-WF and R-WF, which are mainly metabolised by CYP2C9 and 3A4, respectively. 4) Regimens based on the fluoropyrimidine 5-fluorouracil (5-FU) have been the mainstay of chemotherapy for malignancies that include colorectal, [5][6][7][8][9][10][11][12][13] breast, [6][7][8][9][10][11][12] head and neck, 8,12) and gastric cancers. 7,[11][12][13] Several reports in the literature have described possible drug-drug interactions (DDIs) between WF and fluoropyrimidines, [7][8][9][10][11][13][14][15] but the majority of these studies involved oral fluoropyrimidines.…”

Section: Introductionmentioning

confidence: 99%

“…4) Regimens based on the fluoropyrimidine 5-fluorouracil (5-FU) have been the mainstay of chemotherapy for malignancies that include colorectal, [5][6][7][8][9][10][11][12][13] breast, [6][7][8][9][10][11][12] head and neck, 8,12) and gastric cancers. 7,[11][12][13] Several reports in the literature have described possible drug-drug interactions (DDIs) between WF and fluoropyrimidines, [7][8][9][10][11][13][14][15] but the majority of these studies involved oral fluoropyrimidines. Studies documenting 5-FU and WF DDIs discussed the possibility that CYP2C9 inhibition is the main pathway for elevated prothrombin time international normalised ratio (PT-INR) during coadministration.…”

Section: Introductionmentioning

confidence: 99%

Changes in Pharmacodynamic Parameters during Co-administration of 5-FU with Warfarin: A Retrospective Case Series

Tayag

Ishii

Kokuba

et al. 2022

Biological & Pharmaceutical Bulletin

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Drug-drug interactions (DDIs) between warfarin (WF) and fluoropyrimidines are well known. Coadministration of WF and 5-fluorouracil (5-FU) leads to elevations in prothrombin time international normalised ratio (PT-INR). The inhibition of drug metabolism through suppression of CYP activity is a possible cause of prolonged PT-INR elevations. 5-FU and its metabolites are suspected to inhibit CYPs, but the precise mechanisms of action remain unknown. This study aimed to investigate the possible DDI effects of the co-administration of 5-FU with WF using PT-INR and PT-INR/dose ratio as pharmacodynamic parameters. Retrospective case series data were collected from patients who received parenteral 5-FU chemotherapy from April 2009 to December 2019 at the University of the Ryukyus Hospital. Seven patients who received 5-FU in combination with WF were analysed. There was a significant increase in PT-INR and PT-INR/dose during the co-administration of WF and 5-FU ( p 0.0018 and p 0.0187, respectively; paired t-test). The findings demonstrated significant DDI between 5-FU and WF evident as elevated PT-INR and PT-INR/dose ratio.

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“…7 The effects of drug interactions have been reported for 5-FU, capecitabine and S-1. 8 A prolonged prothrombin time was observed in patients taking WF with a fluoropyrimidine, such as S-1, due to drugdrug interactions via CYP2C9. 9 Therefore, close monitoring of the prothrombin time international normalized ratio (PT-INR) is required to adjust the WF dose.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the anticoagulant effect and timing of the concomitant use of S-1 and warfarin

et al. 2016

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ObjectivesTo evaluate the effects of the timing of warfarin (WF) administration in patients with gastric cancer who received S-1 oral chemotherapy.MethodsThis retrospective chart review collected patient data including the prothrombin time international normalized ratio (PT-INR). Patients were categorized into three groups based on the timing of WF administration in relation to S-1 oral chemotherapy: group A patients received WF before S-1 chemotherapy; group B patients started WF during S-1 chemotherapy; and group C patients started WF after completing S-1 chemotherapy.ResultsA total of 21 patients with gastric cancer were included in the study; group A (n = 8), group B (n = 10) and group C (n = 3). Seven patients (88%) in group A, seven (70%) in group B and all of the patients (100%) in group C had >2.5 PT-INR. There was no significant difference in the time-to-exceed 2.5 PT-INR between groups A and B.ConclusionsThese findings suggest that the timing of WF use in relation to S-1 chemotherapy might not be an important factor for PT-INR, although the low patient numbers included in the study should be taken into consideration.

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Impact of capecitabine and S-1 on anticoagulant activity of warfarin in patients with gastrointestinal cancer

Abstract: The anticoagulant activity of warfarin may be enhanced by coadministration with capecitabine or S-1. Close monitoring of anticoagulant activity is required to avoid a hyperfibrinolytic state due to a severe adverse interaction.

Cited by 5 publications

References 30 publications

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

Changes in Pharmacodynamic Parameters during Co-administration of 5-FU with Warfarin: A Retrospective Case Series

Evaluation of the anticoagulant effect and timing of the concomitant use of S-1 and warfarin

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