A Drug Interaction between Crizotinib and Warfarin in Non-Small-Cell Lung Cancer: A Case Report

Kubomura, Yu; Ise, Yuya; Wako, Tetsuya; Katayama, Shirou; Noro, Rintaro; Kubota, Keiichi

doi:10.1272/jnms.84.291

Cited by 5 publications

(2 citation statements)

References 10 publications

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“…13,69 Coadministration of crizotinib increases the AUC and C max values for midazolam (a sensitive CYP3A substrate), by 116% and 32%, 265% and 102%, and 250% and 139%, on average, at crizotinib dose levels of 100 mg daily, 250 mg twice daily, and 300 mg twice daily, respectively, suggesting that crizotinib is a moderate CYP3A inhibitor. 29,69 The warfarin (R) enantiomer is metabolized by CYP3A4, kubomura et al 70 reported a case of increased prothrombin time-international normalized ratio when crizotinib and warfarin were coadministered. Therefore, the concomitant use of crizotinib with sensitive CYP3A substrates should be avoided, if the concomitant use of crizotinib is unavoidable, reducing the dose of CYP3A substrates is recommended.…”

Section: Crizotinibmentioning

confidence: 99%

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

Zhao¹,

Chen²,

Chu

et al. 2020

DDDT

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Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug Administration and/or the European Medicines Agency for use during the treatment of ALKgene-rearrangement forms of NSCLC. Although the oral route of administration is convenient and results in good compliance among patients, oral administration can be affected by many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and p-glycoprotein. These factors can result in increased risks for serious adverse events or can lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes the pharmacokinetic parameters and drug-drug interactions associated with ALK-TKIs to provide specific recommendations for oncologists and clinical pharmacists when prescribing ALK-TKIs.

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Section: Crizotinibmentioning

confidence: 99%

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

Zhao¹,

Chen²,

Chu

et al. 2020

DDDT

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“…Statements on drug interactions between warfarin and alectinib or crizotinib are not available in the prescription information for these drugs. Although some studies have reported on the drug interactions between warfarin and each of the above-mentioned ALK-TKIs [ 5 – 7 ], INR elevation during treatment with alectinib, crizotinib, or ceritinib concurrent use of warfarin and bucolome has not been reported. Here, we report the first case of a patient receiving warfarin and bucolome whose INR increased after sequential treatment with alectinib, crizotinib, and ceritinib.…”

Section: Introductionmentioning

confidence: 99%

Drug interactions between ALK inhibitors and warfarin with concurrent use of bucolome: a case report

Kato

Kunimoto

Kitagawa

et al. 2023

J Pharm Health Care Sci

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Background Alectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking. Case presentation. We report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2–3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake. Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome. Conclusions Close monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.

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Clinical Pharmacokinetics of Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer

2018

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The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug-drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1-4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood-brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.

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A Drug Interaction between Crizotinib and Warfarin in Non-Small-Cell Lung Cancer: A Case Report

Cited by 5 publications

References 10 publications

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

Drug interactions between ALK inhibitors and warfarin with concurrent use of bucolome: a case report

Clinical Pharmacokinetics of Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer

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