Effect of gefitinib on warfarin antithrombotic activity

Arai, Setsuo; Mitsufuji, Hisashi; Nishii, Yasuto; Onoda, Shoichi; Ryuge, Shinichiro; Wada, Mayuko; Katono, Ken; Iwasaki, Maiko; Takakura, Akira; Otani, Sakiko; Yamamoto, Michiko; Yanaihara, Tomoko; Yokoba, Masanori; Kubota, Minoru; Katagiri, Masayuki; Fukui, Tomoya; Kobayashi, Hirosuke; Yanase, Nobuo; Hataishi, Ryuji; Masuda, Noriyuki

doi:10.1007/s10147-008-0871-2

Cited by 18 publications

(13 citation statements)

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“…With regard to the degree of INR elevation (60-80% increase from the baseline INR, on median) and the time until onset of INR elevation (within two weeks), our findings were similar to those reported in the gefitinib studies previously. 17 However, the time until onset showed a wide interindividual variation, ranging from 4 to 22 days in the gefitinib group and 2 to 62 days in the erlotinib group. The schedule for INR measurement would have affected the predefined day of onset of drug interaction, and INR elevation may have occurred before INR monitoring, especially in an outpatient setting.…”

Section: Discussionmentioning

confidence: 95%

“…The prevalence of warfarin-gefitinib interaction observed in our study (83%) was higher than that reported previously (50%). 17 Arai et al studied INR in 12 patients during the first two weeks after the start of concomitant warfarin and gefitinib administration. Although they did not show the definition of INR elevation in their report, their definition might differ from ours (an increase in INR of more than 20% from the baseline value).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, characteristics of INR elevation after concomitant administration of warfarin and TKIs, such as its frequency, degree, onset time, and changes of the time in the therapeutic range (TTR), are obscure and the mechanisms responsible for warfarin-TKI interaction remain totally unknown at present, as most publications dealing with this issue have been limited to case reports. [17][18][19][20] One of the goals of the present study was to assess the effects of drug-drug interaction between warfaringefitinib or -erlotinib therapy, such as the frequency, degree, onset of INR elevation, and TTR by examining the changes in INR. In addition, using human liver microsomes in vitro, we examined the effects of these two TKIs on the 7-hydroxylation of (S)-warfarin as a marker activity for CYP2C9.…”

Section: Introductionmentioning

confidence: 99%

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Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity

Hiraide

Minowa

Nakano

et al. 2018

J Oncol Pharm Pract

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BackgroundElevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib.ObjectiveTo assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity.MethodsThis retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study.ResultsCompared with international normalized ratio at the baseline significant ( P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing.ConclusionIn most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity

Hiraide

Minowa

Nakano

et al. 2018

J Oncol Pharm Pract

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“…There are a few studies on pharmacokinetic interactions between gefitinib and herbal products. The most of pharmacokinetic studies have shown significant interactions between gefitinib and warfarin (Arai et al, 2009), an herbal medicines with ginseng, mushrooms and selenium (Hwang et al, 2008) and Marsdeniatenacissima extract (Han et al, 2014), which result in reduced anti-tumor effects of gefitinib or reduced efficacy of combined drugs. Here, co-administration with BJIKT appeared to influence little in the oral bioavailability of gefitinib, although BJIKT include ginseng and other 9 herbs.…”

Section: Discussionmentioning

confidence: 99%

Effects of Bojungikkitang (a Polyherbal Formula), on Gefitinib Pharmacokinetics in Rats

Hyun¹,

Kim²,

Park³

et al. 2015

International J. of Pharmacology

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is mainly used for treatment of non-small cell lung cancers and breast cancers, but many researcher have been interested in the combination therapies due to gefitinib-related toxicities. Bojungikkitang (BJIKT) is a traditional Korean herbal medicine for various tonic effects in patients with poor gastrointestinal functions and conditions debilitated from chronic diseases, which suggests possibility to improve cachexia in cancer patients or the immune system as an adjunctive therapy. Therefore, the pharmacokinetic interactions between gefitinib and BJIKT were examined as a first screening for the combination therapy. One batch of 10 rats received single oral co-administration of gefitinib with BJIKT (combination) or with distilled water (control). Another batch of 10 rats received repeated oral administration of the combination for 9 days after pretreatments with BJIKT for 7 days or control for 9 days after pretreatments with distilled water for 7 days. In the single and repeated co-administration, the gefitinib and BJIKT were used at doses of 50 and 100 mg kgG 1 , respectively and the co-administration with BJIKT or distilled water was performed within 5 min after gefitinib. The plasma samples were collected time-dependently after the single administration and the initial and last treatment of the repeated administration. The analyzed pharmacokinetic parameters included peak concentration (C max), time to reach the C max , area under the plasma concentration-time curve, half-life and mean residence time to infinity. In the single administration, the gefitinib kinetic curves of plasma concentration were not different between the both of combination and control. There were no differences in the pharmacokinetic parameters between the both. It suggests little interactions between gefitinib and BJIKT. In addition, there were no interactions between gefitinib and BJIKT in the single co-administration after pretreatments for 7 days and even after the repeated co-administration for 9 days. This study provides basic information for the combination therapy of gefitinib with BJIKT.

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“…Increases in the international normalized ratio (INR) and/or the rate of bleeding events have occurred in patients taking warfarin and gefitinib concomitantly 72,73,89. Patients taking this combination should be monitored regularly for changes in prothrombin time or INR 72,73…”

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

<p>Comparative review of drug–drug interactions with epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer</p>

Xu¹,

Li²

2019

OTT

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The development of small-molecule tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) has revolutionized the management of non-small-cell lung cancer (NSCLC). Because these drugs are commonly used in combination with other types of medication, the risk of clinically significant drug–drug interactions (DDIs) is an important consideration, especially for patients using multiple drugs for coexisting medical conditions. Clinicians need to be aware of the potential for clinically important DDIs when considering therapeutic options for individual patients. In this article, we describe the main mechanisms underlying DDIs with the EGFR-TKIs that are currently approved for the treatment of NSCLC, and, specifically, the potential for interactions mediated via effects on gastrointestinal pH, cytochrome P450-dependent metabolism, uridine diphosphate-glucuronosyltransferase, and transporter proteins. We review evidence of such DDIs with the currently approved EGFR-TKIs (gefitinib, erlotinib, afatinib, osimertinib, and icotinib) and discuss several information sources that are available online to aid clinical decision-making. We conclude by summarizing the most clinically relevant DDIs with these EFGR-TKIs and provide recommendations for managing, minimizing, or avoiding DDIs with the different agents.

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Effect of gefitinib on warfarin antithrombotic activity

Cited by 18 publications

References 18 publications

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity

Effects of Bojungikkitang (a Polyherbal Formula), on Gefitinib Pharmacokinetics in Rats

<p>Comparative review of drug–drug interactions with epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer</p>

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