Characterization of HKI-272 Covalent Binding to Human Serum Albumin

Wang, Jianyao; Li-Chan, Xiao Xian; Atherton, Jim; Deng, Lin; Espina, Robert; Yu, Linning; Horwatt, Peter; Ross, Steven M.; Lockhead, Susan; Ahmad, Syed Sayeed; Chandrasekaran, Appavu; Oganesian, Aram; Scatina, JoAnn; Mutlib, Abdul; Talaat, Rasmy E.

doi:10.1124/dmd.110.032292

Cited by 55 publications

(40 citation statements)

References 23 publications

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“…The mean elimination half-life (t ½ ) after a 240 mg dose of neratinib with food was approximately 14 hours [61] which supports a once-daily dosing regimen. Binding studies show that neratinib binds reversibly to human serum albumin [67]. The pharmacokinetics of neratinib in Japanese patients [62] were similar to those observed in a US population [61] (Table 2).…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 56%

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Kourié

Chaix

Gombos

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

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Section: Pharmacokinetics and Metabolismmentioning

confidence: 56%

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Kourié

Chaix

Gombos

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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“…Although the potential exists for allergic reactions if the drug acts like a hapten, this has not been observed in patients receiving afatinib. Covalent binding to human serum albumin has also been reported for another HER-2 tyrosine kinase inhibitor HKI-272 with a structure closely related to afatinib [19].…”

Section: Discussionmentioning

confidence: 92%

Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers

Stopfer¹,

Marzin²,

Narjes³

et al. 2011

Cancer Chemother Pharmacol

121

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“…Covalent binding to albumin has been shown to cause incomplete extraction recovery of several highly plasma protein-bound drugs from human plasma, including thymoquinone and neratinib (HKI-271) [14, 15]. Neratinib is a potent irreversible tyrosine kinase inhibitor of the ErbB family of receptors (HER1, HER2, and HER4), which covalently binds to the cytoplasmic domain of ErbB receptors, thereby preventing downstream signaling [16].…”

Section: Resultsmentioning

confidence: 99%

“…Neratinib is a potent irreversible tyrosine kinase inhibitor of the ErbB family of receptors (HER1, HER2, and HER4), which covalently binds to the cytoplasmic domain of ErbB receptors, thereby preventing downstream signaling [16]. It has been shown that the incomplete recovery of nerotinib from human plasma after exhaustive extraction with organic solvent was caused by the covalent binding of the drug to the lysine residue (Lys190) of HSA via Michael addition [15]. Lys190 is located at the junction of domains I (1–188) and II (189–385) of HSA, a high-affinity region for substrate protein binding [17, 18].…”

Section: Resultsmentioning

confidence: 99%

A stable isotope-labeled internal standard is essential for correcting for the interindividual variability in the recovery of lapatinib from cancer patient plasma in quantitative LC–MS/MS analysis

Wiegand

LoRusso

et al. 2013

Journal of Chromatography B

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The development and validation of a LC-MS/MS method is often performed using pooled human plasma, which may fail to account for variations in interindividual matrices. Since calibrator standards and quality control samples are routinely prepared in pooled human plasma, variations in the extraction recovery and/or matrix effect between pooled plasma and individual patient plasma can cause erroneous measurements. Using both pooled human plasma as well as individual healthy donor and cancer patient plasma samples, we evaluated the analytical performance of two classes of internal standards (i.e., non-isotope-labeled and isotope-labeled) in the quantitative LC-MS/MS analysis of lapatinib. After exhaustive extraction with organic solvent, the recovery of lapatinib, a highly plasma protein-bound drug, varied up to 2.4-fold (range, 29 – 70%) in 6 different donors of plasma and varied up to 3.5-fold (range, 16 – 56%) in the pretreatment plasma samples from 6 cancer patients. No apparent matrix effects were observed for lapatinib in both pooled and individual donor or patient plasma samples. The calibration curve range was 5 – 5000 ng/ml of lapatinib in plasma. Both the non-isotope-labeled (zileuton) and isotope-labeled (lapatinib-d3) internal standard methods showed acceptable specificity, accuracy (within 100 ± 10%), and precision (< 11%) in the determination of lapatinib in pooled human plasma. Nevertheless, only the isotope-labeled internal standard could correct for the interindividual variability in the recovery of lapatinib from patient plasma samples. As inter- and intra-patient matrix variability is commonly presented in the clinical setting, this study provides an example underscoring the importance of using a stable isotope-labeled internal standard in quantitative LC-MS/MS analysis for therapeutic drug monitoring or pharmacokinetic evaluation.

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Characterization of HKI-272 Covalent Binding to Human Serum Albumin

Abstract: ABSTRACT:The study was initiated as an observation of incomplete extraction recovery of N-(4- (

Cited by 55 publications

References 23 publications

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers

A stable isotope-labeled internal standard is essential for correcting for the interindividual variability in the recovery of lapatinib from cancer patient plasma in quantitative LC–MS/MS analysis

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