Risk factors associated with the incidence and time to onset of lapatinib-induced hepatotoxicity

Moon, Jin Young; Han, Ji Min; Seo, Inyoung; Gwak, Hye Sun

doi:10.1007/s10549-019-05382-x

Cited by 9 publications

(4 citation statements)

References 19 publications

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“…Therefore, the present results, which focused on patient‐oriented outcome, might be much closer to what happens in real clinical practice. For potential underlying mechanisms, investigators speculated that H2RAs might predispose intestinal bacterial overgrowth and cause the transformation of primary bile acids to secondary bile acids 74 and that H2RAs inhibited cytochrome P450 enzymes, influenced drug metabolism, and subsequently exerted liver damage 75–77 . However, it should be noted that the individual studies included in the current review were mainly based on UK and Taiwan data sets, and further multiethnic sample‐based trials are therefore still needed for further clarifying these issues.…”

Section: Discussionmentioning

confidence: 97%

“…For potential underlying mechanisms, investigators speculated that H2RAs might predispose intestinal bacterial overgrowth and cause the transformation of primary bile acids to secondary bile acids 74 and that H2RAs inhibited cytochrome P450 enzymes, influenced drug metabolism, and subsequently exerted liver damage. [75][76][77] However, it should be noted that the individual studies included in the current review were mainly based on UK and Taiwan data sets, and further multiethnic sample-based trials are therefore still needed for further clarifying these issues. For gastric cancer outcomes, our review verified that use of H2RAs could increase the probability of its occurrence, which, similar to gastrointestinal infection, might also be attributed to the gastric mucosa hyperplastic effects of gastrin induced by H2RAs.…”

Section: Discussionmentioning

confidence: 99%

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Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta‐Analyses

Meng

Chen

Zhang

et al. 2022

The Journal of Clinical Pharma

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Histamine H2 receptor antagonists (H2RAs) were widely used to inhibit gastric acid secretion, but its association with adverse events remains controversial and unclear. We conducted an umbrella review of meta-analyses to systematically assess the quality and credibility of the correlations between H2RA use with the risk of adverse outcomes through searching 4 major databases from inception to April 30, 2022. Forty-six individual metaanalyses were identified, including 29 meta-analyses of observation studies with 32 unique outcomes and 19 meta-analyses of randomized controlled trials with 3 unique outcomes for comparing the H2RA versus non-H2RA group. A Measurement Tool to Assess Systematic Reviews 2 rating for the included meta-analyses showed that 4 of 46 meta-analyses were assigned as high scores, 3 were assigned as "moderate," and 25 were assigned as low scores. Grading of Recommendations Assessment, Development and Evaluation assessment for combined results demonstrated that 6 outcomes were rated as "moderate," 9 outcomes were rated as "low," and 17 outcomes were rated as "very low." We confirmed significant associations of H2RA use with pneumonia, peritonitis, necrotizing enterocolitis, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, or common reproductive system cancer or renal, neurological, and cardiovascular system diseases were observed. We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta‐Analyses

Meng

Chen

Zhang

et al. 2022

The Journal of Clinical Pharma

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“…Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), gastrointestinal stromal tumors (GIST), or other malignancies were orally administered imatinib (100-800 mg/day) ( 21 ). Patients with metastatic breast cancer were orally administered lapatinib (750-1250 mg/day) ( 22 ). In all five studies, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured before initiation of TKI therapy and then every two to three months thereafter.…”

Section: Methodsmentioning

confidence: 99%

A Risk Scoring System Utilizing Machine Learning Methods for Hepatotoxicity Prediction One Year After the Initiation of Tyrosine Kinase Inhibitors

Han¹,

Yee²,

Cho³

et al. 2022

Front. Oncol.

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BackgroundThere is currently no method to predict tyrosine kinase inhibitor (TKI) -induced hepatotoxicity. The purpose of this study was to propose a risk scoring system for hepatotoxicity induced within one year of TKI administration using machine learning methods.MethodsThis retrospective, multi-center study analyzed individual data of patients administered different types of TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib) selected in five previous studies. The odds ratio and adjusted odds ratio from univariate and multivariate analyses were calculated using a chi-squared test and logistic regression model. Machine learning methods, including five-fold cross-validated multivariate logistic regression, elastic net, and random forest were utilized to predict risk factors for the occurrence of hepatotoxicity. A risk scoring system was developed from the multivariate and machine learning analyses.ResultsData from 703 patients with grade II or higher hepatotoxicity within one year of TKI administration were evaluated. In a multivariable analysis, male and liver metastasis increased the risk of hepatotoxicity by 1.4-fold and 2.1-fold, respectively. The use of anticancer drugs increased the risk of hepatotoxicity by 6.0-fold. Patients administered H2 blockers or PPIs had a 1.5-fold increased risk of hepatotoxicity. The area under the receiver-operating curve (AUROC) values of machine learning methods ranged between 0.73-0.75. Based on multivariate and machine learning analyses, male (1 point), use of H2 blocker or PPI (1 point), presence of liver metastasis (2 points), and use of anticancer drugs (4 points) were integrated into the risk scoring system. From a training set, patients with 0, 1, 2-3, 4-7 point showed approximately 9.8%, 16.6%, 29.0% and 61.5% of risk of hepatotoxicity, respectively. The AUROC of the scoring system was 0.755 (95% CI, 0.706-0.804).ConclusionOur scoring system may be helpful for patient assessment and clinical decisions when administering TKIs included in this study.

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“…The main side effects of LAP include hepatotoxicity, diarrhea, rash, pruritus, and nausea. In particular, LAPinduced hepatotoxicity is idiosyncratic in nature (Castellino et al 2012;Moon et al 2019;Rayane Mohamed 2018). It has been pointed out that the reactive metabolites may be responsible for direct or indirect toxicity to cellular proteins or DNA; however, the underlying mechanisms remain unclear (Parham et al 2016;Spraggs et al 2011).…”

Section: Introductionmentioning

confidence: 99%

In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor

et al. 2020

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The epidermal growth factor receptors EGFR and HER2 are the main targets for tyrosine kinase inhibitors (TKIs). The quinazoline derivative lapatinib (LAP) is used since 2007 as dual TKI in the treatment of metastatic breast cancer and currently, it is used as an oral anticancer drug for the treatment of solid tumors such as breast and lung cancer. Although hepatotoxicity is its main side effect, it makes sense to investigate the ability of LAP to induce photosensitivity reactions bearing in mind that BRAF (serine/threonine-protein kinase B-Raf) inhibitors display a considerable phototoxic potential and that afloqualone, a quinazoline-marketed drug, causes photodermatosis. Metabolic bioactivation of LAP by CYP3A4 and CYP3A5 leads to chemically reactive N-dealkylated (N-LAP) and O-dealkylated (O-LAP) derivatives. In this context, the aim of the present work is to explore whether LAP and its N-and O-dealkylated metabolites can induce photosensitivity disorders by evaluating their photo(geno)toxicity through in vitro studies, including cell viability as well as photosensitized protein and DNA damage. As a matter of fact, our work has demonstrated that not only LAP, but also its metabolite N-LAP have a clear photosensitizing potential. They are both phototoxic and photogenotoxic to cells, as revealed by the 3T3 NRU assay and the comet assay, respectively. By contrast, the O-LAP does not display relevant photobiological properties. Remarkably, the parent drug LAP shows the highest activity in membrane phototoxicity and protein oxidation, whereas N-LAP is associated with the highest photogenotoxicity, through oxidation of purine bases, as revealed by detection of 8-Oxo-dG.

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Risk factors associated with the incidence and time to onset of lapatinib-induced hepatotoxicity

Cited by 9 publications

References 19 publications

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta‐Analyses

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta‐Analyses

A Risk Scoring System Utilizing Machine Learning Methods for Hepatotoxicity Prediction One Year After the Initiation of Tyrosine Kinase Inhibitors

In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor

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