Prophylactic use of antidiarrheal agents to control diarrhea associated with lapatinib therapy in breast cancer patients.

Jamil, Muhammad Omer; Rizwan, Maira; Carpenter, John T.

doi:10.1200/jco.2015.33.29_suppl.205

Cited by 5 publications

(3 citation statements)

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“…The most common SE of lapatinib is diarrhea, which causes dehydration and was observed in nearly half of the patients treated with the drug. The occurrence of such symptoms as: moderate to severe diarrhea, severe nausea or vomiting, and severe cramping, significantly reduces the patientís quality of life and causes the need to stop taking the drug until recovery and then reduce its dose (36). However, it is known that the development of diarrhea is related to the oral dose rather than the drug plasma concentration (37).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction After Oral Coadministration of Clarithromycin and the Tyrosine Kinase Inhibitor Lapatinib in Rats

Karbownik¹,

Porażka²,

Łuczak³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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Lapatinib is a tyrosine kinase inhibitor used to treat patients with locally advanced or metastatic breast cancer exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2 receptor, ErbB2). Preclinical and clinical studies suggest that lapatinib is mainly metabolized by CYP3A4, therefore the study in an animal model was designed to investigate the pharmacokinetic interaction of lapatinib and clarithromycin, a well-known CYP3A4 inhibitor. The rats were subjected to one of the two study groups: lapatinib + clarithromycin (I Lap+Clar ; n = 6), and lapatinib + placebo (II Lap ; n = 6). The animals were treated with lapatinib in the oral single dose of 100 mg/kg. The antibiotic was administered orally at a dose of 25 mg/kg. Blood sampling was performed until 30 hours after dosing for pharmacokinetic assays. Plasma concentrations of lapatinib were measured by liquid chromatography-mass spectrometry. The comparison of lapatinib maximum concentration and area under the concentration-time curve in the I Lap+Clar with the control group II Lap gave the ratios of 1.38 (90% confidence interval (CI)) (1.14; 1.68) and 1.16 (0.75; 1.79), respectively. A statistically significant difference between analyzed groups was revealed only for maximum concentration (p = 0.0107). Single oral administration of clarithromycin significantly increased the concentration of lapatinib in rats, therefore caution should be taken during concomitant treatment with this macrolide and the tyrosine kinase inhibitor in patients.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction After Oral Coadministration of Clarithromycin and the Tyrosine Kinase Inhibitor Lapatinib in Rats

Karbownik¹,

Porażka²,

Łuczak³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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“…Additionally, there are currently no speci c clinical guidelines for managing LID owing to a lack of research, while CID has several guidelines, such as those of the European Society for Medical Oncology (ESMO) and the US National Comprehensive Cancer Centre Network 6 . Typically, antidiarrhoeal agents such as loperamide and octreotide are used to manage diarrhoea 7 . However, neither antidiarrhoeal agent su ciently reduces diarrhoea and can result in severe constipation and nausea 6 .…”

Section: Introductionmentioning

confidence: 99%

Lapatinib-induced ErbB1 Inhibition Modulates Caco-2 Intestinal Permeability Through Tight Junction Alteration

Zain,

Sharin,

Khan

et al. 2023

Preprint

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Lapatinib (LAP), a dual ErbB1 and ErbB2 tyrosine kinase inhibitor, is effective in ErbB2-positive breast cancer treatment but is associated with diarrhoea. ErbB1 is expressed in the intestine; thus, it is hypothesised that lapatinib inhibits normal ErbB1 function, causing diarrhoea. This study investigated the possible involvement of ErbB1 inhibition in the underlying mechanism of lapatinib-induced diarrhoea. Caco-2 intestinal monolayers were treated with LAP and LAP in combination with recombinant epidermal growth factor (LAP+rEGF). Transepithelial electrical resistance (TEER) of the Caco-2 monolayer and paracellular transport of Lucifer yellow were measured, while the expression of the tight junction proteins (TJPs) claudin-1, occludin, and ZO-1 and the inflammatory cytokines TNF-α, IL-1β, and IL-6 were determined using qPCR and immunofluorescence staining. LAP significantly decreased TEER compared to the control untreated monolayer (p < 0.05) at 96 hours. Higher Lucifer yellow permeability was observed in the LAP group but was not significantly different from that in the control group. LAP suppressed the mRNA and protein expression of TJPs, whereas cotreatment with rEGF counteracted LAP inhibition (p < 0.05). No significant changes were observed in the mRNA expression levels of inflammatory cytokines in the LAP group. Surprisingly, rEGF treatment increased IL-6 mRNA expression (p < 0.01). However, it is suggested that IL-6 is involved in intestinal epithelial proliferation induced by rEGF rather than inflammation. Lapatinib increased Caco-2 intestinal monolayer permeability and reduced tight junction expression by inhibiting ErbB1 expression, suggesting a mechanism of lapatinib-induced diarrhoea.

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“…Although diarrhoea seems common, it is often severe enough to require a break in treatment or a dose reduction [ 6 ]. Diarrhoea in lapatinib administration was evident as early as 7 days of the treatment course and has been managed usually with antidiarrhoeal agents depending on the treatment protocol [ 69 ]. However, it is hypothesised that the development of lapatinib-induced diarrhoea differs from conventional chemotherapy-induced diarrhoea and is not due to direct cytotoxicity but through alternative mechanisms [ 70 ].…”

Section: Introductionmentioning

confidence: 99%

Role of ErbB1 in the Underlying Mechanism of Lapatinib-Induced Diarrhoea: A Review

Sharin

Khan

Ibahim

et al. 2022

BioMed Research International

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Lapatinib, an orally administered small-molecule tyrosine kinase inhibitor (SM-TKI), is an effective treatment for ErbB2-positive breast cancer. However, its efficacy as one of the targeted cancer therapies has been hampered by several adverse effects, especially gastrointestinal toxicity, commonly manifested as diarrhoea. Although it can be generally tolerated, diarrhoea is reported as the most common and most impactful on a patient’s quality of life and associated with treatment interruption. Severe diarrhoea can result in malabsorption, leading to dehydration, fatigue, and even death. ErbB1 is an epidermal growth factor profoundly expressed in normal gut epithelium while lapatinib is a dual ErbB1/ErbB2 tyrosine kinase inhibitor. Thus, ErbB1 inhibition by lapatinib may affect gut homeostasis leading to diarrhoea. Nevertheless, the underlying mechanisms remain unclear. This review article provides evidence of the possible mechanisms of lapatinib-induced diarrhoea that may be related to/or modulated by ErbB1. Insight regarding the involvement of ErbB1 in the pathophysiological changes such as inflammation and intestinal permeability as the underlying cause of diarrhoea is covered in this article.

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Prophylactic use of antidiarrheal agents to control diarrhea associated with lapatinib therapy in breast cancer patients.

Cited by 5 publications

References 0 publications

Pharmacokinetic Interaction After Oral Coadministration of Clarithromycin and the Tyrosine Kinase Inhibitor Lapatinib in Rats

Pharmacokinetic Interaction After Oral Coadministration of Clarithromycin and the Tyrosine Kinase Inhibitor Lapatinib in Rats

Lapatinib-induced ErbB1 Inhibition Modulates Caco-2 Intestinal Permeability Through Tight Junction Alteration

Role of ErbB1 in the Underlying Mechanism of Lapatinib-Induced Diarrhoea: A Review

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