Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry

Zhu, Yunting; Li, Liang; Zhang, Ge; Wan, Hong; Yang, Changyong; Diao, Xingxing; Chen, Xiaoyan; Zhang, Lianshan; Zhong, Dafang

doi:10.1016/j.jchromb.2016.08.009

Cited by 65 publications

(72 citation statements)

References 25 publications

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“…Pyrotinib was administered within 30 minutes after breakfast in the morning; the capecitabine dose was split into two equal doses and administered every 12 hours. The initial dose of pyrotinib was based on preclinical data (14,15) and on the results of a phase I monotherapy study in patients with breast cancer (16) in China. The study reported an MTD for pyrotinib monotherapy as 400 mg daily.…”

Section: Study Treatment and Dose-escalation Protocolmentioning

confidence: 99%

“…Pyrotinib is an oral, irreversible pan-ErbB tyrosine kinase inhibitor (TKI) that potently inhibits EGFR/HER1, HER2, and HER4 (13). Preclinical data of pyrotinib demonstrate effective proliferation inhibition of HER2-overexpressing cells both in vivo and in vitro (14,15). In a phase I pyrotinib monotherapy study (16), the MTD of pyrotinib was determined to be 400 mg daily.…”

Section: Introductionmentioning

confidence: 99%

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Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Guan

Chen

et al. 2019

Clinical Cancer Research

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Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2positive metastatic breast cancer (MBC).Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers.Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumabpretreated patients and 90.9% (10/11) in trastuzumab-na€ ve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P ¼ 0.006).Conclusions: In a population largely na€ ve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.

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Section: Study Treatment and Dose-escalation Protocolmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Guan

Chen

et al. 2019

Clinical Cancer Research

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“…It should be noted that M18 was eluted much later than the parent under the acidic mobile phase system, which suggested the formation of lactam. Metabolite with lactam formation displayed prolonged chromatographic retention under acidic mobile phase system due to the reduced alkalinity . To confirm this deduction, the reference standard of GS‐9620 lactam was bio‐synthesized.…”

Section: Resultsmentioning

confidence: 92%

Metabolism of vesatolimod in rat, dog, and human liver microsomes: Metabolic stability assessment, metabolite identification, and interspecies comparison

Zhang

Wang

et al. 2018

Drug Testing and Analysis

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Vesatolimod (GS-9620) is an agonist of toll-like receptor (TLR7) 7, which has been developed as an anti-hepatitis B virus (HBV) agent. The focus of the present study is on the metabolic stability evaluation and metabolite identification of GS-9620 in rat, dog, and human liver microsomes, as well as interspecies comparison. The average observed in vitro T values were 3.06, 13.06, and 15.56 minutes in rat, dog, and human liver microsomes, respectively. The findings suggested that GS-9620 was rapidly metabolized in the presence of reductive nicotinamide adenine dinucleotide phosphate (NADPH) in rat liver microsomes (RLM), and moderately metabolized in dog liver microsomes (DLM) and human liver microsomes (HLM). Subsequently, the metabolites were characterized using an ultra-high performance liquid chromatography coupled with linear ion trap orbitrap tandem mass spectrometer (UHPLC-LTQ-Orbitrap-MS) with dd-MS on-line data acquisition mode. Under the current conditions, a total of 18 metabolites were detected and their identities were proposed by comparing their accurate masses, fragmental ions, and retention times with those of GS-9620. Three metabolites (M2, M4, and M18) were authentically identified by using reference standards. In RLM, 16 metabolites were identified with M2 being the most abundant metabolite. M4, M5, and M9 were rat-specific. In DLM, 12 minor metabolites were identified with a dog-specific metabolite (M6). In HLM, GS-9620 showed similar metabolic profiles to that in DLM, and 11 minor metabolites were detected with M12 being human-specific. Based on the identified metabolites, the metabolic pathways of GS-9620 were proposed, including hydroxylation, bis-hydroxylation, dehydrogenation, and oxidative deamination.

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“…The formation of this metabolite was not dependent on NADPH. Numerous studies have shown that Michael acceptors are reactive [26,27]. However, it is not clear whether the obacunone-derived toxicity is associated with this functional group.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Metabolic Activation of Obacunone, A Bioactive and Potentially Hepatotoxic Constituent of Dictamni Cortex

et al. 2020

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AbstractObacunone is one of the major bioactive constituents from Dictamni cortex, a traditional Chinese medicine widely used in China. Oral administration of obacunone or Dictamni cortex extract has been shown to cause liver injury in rats. Given that obacunone contains a furan ring, which is a structural alert, metabolic activation might be responsible for obacunone-induced liver injury. In this study, bioactivation pathways of obacunone in rat and human liver microsomes were investigated. Obacunone was first metabolized into cis-butene-1,4-dial, and then cis-butene-1,4-dial was captured by glutathione, N-acetyl-cysteine, and N-acetyl-lysine in the microsomal incubation system. A total of 13 adducts derived from the reaction of cis-butene-1,4-dial with glutathione and/or N-acetyl-lysine were detected and structurally identified by liquid chromatography coupled to high-resolution tandem mass spectrometry. The major metabolite (M7) was identified to be the cyclic mono-glutathione conjugate of cis-butene-1,4-dial, which was detected in bile and urine of obacunone-treated rats. M9 and M10, obacunone-derived glutathione-cis-butene-1,4-dial-NAL conjugates, were detected in the microsomal incubations of obacunone fortified with glutathione and N-acetyl-lysine as trapping agents. M3 and M4, pyrroline-2-one derivatives, were also detected in microsomal incubations. Further phenotyping studies indicated that ketoconazole showed a strong inhibitory effect on the production of cis-butene-1,4-dial in a concentration-dependent manner. CYP3A4 was demonstrated to be the primary enzyme responsible for the bioactivation of obacunone by using individual recombinant human CYP450 enzymes. The current study provides an overview of CYP450-dominated bioactivation of obacunone and contributes to the understanding of the role of bioactivation in obacunone-induced liver injury.

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Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry

Cited by 65 publications

References 25 publications

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Metabolism of vesatolimod in rat, dog, and human liver microsomes: Metabolic stability assessment, metabolite identification, and interspecies comparison

In Vitro and In Vivo Metabolic Activation of Obacunone, A Bioactive and Potentially Hepatotoxic Constituent of Dictamni Cortex

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