Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction

Zhang, Tianhong; Zhang, KeRong; Ma, Li; Li, Zheng; Wang, Juan; Zhang, Yunxia; Lu, Chuang; Zhu, Mingshe; Zhuang, Xiaomei

doi:10.1016/j.xphs.2017.12.007

Cited by 5 publications

(7 citation statements)

References 14 publications

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“…Icotinib is a second-generation reversible EGFR-TKI, approved by the China Food and Drug Administration (CFDA) for the treatment of advanced NSCLC following progression on at least one platinum-based chemotherapy 18,29,136,137. To date, relatively few studies have reported on potential DDIs with icotinib 138…”

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

“…A preclinical pharmacokinetic study and a clinical mass balance study showed that more than 90% of icotinib is eliminated by hepatic metabolism, primarily via CYP450 enzymes; four to six main metabolites were identified 139. The main enzymes responsible for icotinib metabolism are CYP3A4, CYP2C19, CYP3A5, and CYP1A2 138,139. According to Shi et al (2013), the involvement of several enzymes in the metabolism of icotinib means that accumulation of the drug is limited, and explains its relatively short half-life (6 h140), which is one of the main differences between icotinib and the other EGFR-TKIs 40…”

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

“…Zhang et al (2018) recently examined the formation of icotinib metabolites by recombinant CYP isozymes in human liver microsomes, to identify the enzymes responsible for icotinib metabolism 138. The metabolic pathways identified in vitro predominantly involved CYP3A4 (accounting for 77–87% of icotinib metabolism), CYP3A5 (5–15%), and CYP1A2 (3.7–7.5%).…”

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

“…Metabolism of icotinib via CYP450 2C8, 2C9, 2C19, and 2D6 was insignificant. The authors recommended that clinicians should consider the risk of DDIs when prescribing icotinib with strong CYP3A inhibitors or inducers 138. Induction of CYP1A2 in lung cancer patients with smoking history may also contribute to the PK and pharmacologic variability of icotinib 138…”

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

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<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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Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

Section: Clinically Relevant Ddis With Selected Egfr-tkismentioning

confidence: 99%

See 2 more Smart Citations

<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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“…Nonsmall cell lung cancer accounts for ~85% of all lung cancer cases; however, its treatment remains a challenge (Zhang et al, ). Icotinib, 4‐[(3‐ethynylphenyl)amino]‐6,7‐benzo‐12‐crown‐4‐quinazoline, as shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

Validation of an LC‐MS/MS method for simultaneous determination of icotinib and its four major circulating metabolites in human plasma and its application in a pharmacokinetic study

Xiao

Maiolino

Yan

et al. 2018

Biomedical Chromatography

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In this study, a simple and sensitive LC-MS/MS method was developed and validated for simultaneous determination of icotinib and its four circulating metabolites in human plasma. The analytes were extracted with acetonitrile and separated on a C column using 2 mm ammonium acetate containing 0.2% formic acid and acetonitrile as mobile phase. The analytes were introduced into the mass spectrometer via an electrospray ionization source operated in positive ion mode. Precursor-to-product transitions were optimized to be m/z 392.2 → 304.1 for icotinib, m/z 424.1 → 278.2 for M1 and M2, m/z 408.2 → 320.1 for M3, m/z 410.2 → 322.1 for M4 and m/z 394.4 → 278.1 for IS. The assay showed good linearity over the concentration ranges of 0.1-600 ng/mL for icotinib and 0.1-200 ng/mL for metabolites, with correlation coefficients >0.994 (r > 0.994). The LLOQ was 0.1 ng/mL for each analyte. The intra- and inter-day precisions (RSD) were ≤12.98% while the accuracy (RE) ranged from -8.76 to 12.01%. No significant matrix effect was observed. The validated method was successfully applied for the pharmacokinetic study of icotinib and its four circulating metabolites in human plasma after oral administration of icotinib at a single dose of 125 mg.

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Overview of Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Targeted Therapy and Supportive Care for Lung Cancer

Anwar¹,

Nguyen²,

Nagasaka³

et al. 2023

JTO Clinical and Research Reports

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Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction

Cited by 5 publications

References 14 publications

<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>

<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>

Validation of an LC‐MS/MS method for simultaneous determination of icotinib and its four major circulating metabolites in human plasma and its application in a pharmacokinetic study

Overview of Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Targeted Therapy and Supportive Care for Lung Cancer

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