Lapatinib-induced hepatitis: A case report

Peroukides, Stavros; Makatsoris, Thomas; Koutras, Angelos; Tsamandas, Athanasios; Onyenadum, A.; Labropoulou-Karatza, Chryssoula; Kalofonos, Haralabos P.

doi:10.3748/wjg.v17.i18.2349

Cited by 26 publications

(14 citation statements)

References 11 publications

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“…There are several reports linking lapatinib use with drug-induced liver injury (Gomez et al, 2008;Peroukides et al, 2011;Spraggs et al, 2012), and lapatinib carries a black box warning. The metabolism of lapatinib in vivo involves both N-and O-dealkylation by CYP3A4, CYP3A5, and to a lesser extent, CYP2C19 and CYP2C8 (Castellino et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

et al. 2013

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Metabolism-dependent inhibition (MDI) of cytochrome P450 (P450) enzymes has the potential to cause clinically relevant drug-drug interactions. In the case of several alkylamine drugs, MDI of P450 involves formation of a metabolite that binds quasi-irreversibly to the ferrous heme iron to form a metabolic intermediate (MI) complex. The specific metabolites coordinately bound to ferrous iron and the pathways leading to MI complex formation are the subject of debate. We describe an approach combining heme iron oxidation with potassium ferricyanide and metabolite profiling to probe the mechanism of MI complex-based CYP3A4 inactivation by the secondary alkylamine drug lapatinib. Ten metabolites formed from lapatinib by CYP3A4-mediated heteroatom dealkylation, Chydroxylation, N-oxygenation with or without further oxidation, or a combination thereof, were detected by accurate mass spectrometry. The abundance of one metabolite, the N-dealkylated nitroso/ oxime lapatinib metabolite (M9), correlated directly with the prevalence or the disruption of the MI complex with CYP3A4. Nitroso/ oxime metabolite formation from secondary alkylamines has been proposed to occur through two possible pathways: (1) sequential N-dealkylation, N-hydroxylation, and dehydrogenation (primary hydroxylamine pathway) or (2) N-hydroxylation with dehydrogenation to yield a nitrone followed by N-dealkylation (secondary hydroxylamine pathway). All intermediates for the secondary hydroxylamine pathway were detected but the primary N-hydroxylamine intermediate of the primary hydroxylamine pathway was not. Our findings support the mechanism of lapatinib CYP3A4 inactivation as MI complex formation with the nitroso metabolite formed through the secondary hydroxylamine and nitrone pathway, rather than by N-dealkylation to the primary amine followed by N-hydroxylation and dehydrogenation as is usually assumed.

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Section: Introductionmentioning

confidence: 99%

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

et al. 2013

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“…Lapatinib was withheld, and liver biopsy revealed acute hepatitis with macrophage and eosinophilic infiltrate, consistent with drug-induced injury. 18 The patient stopped the study treatment, and her hepatic function returned to normal with oral steroid treatment.…”

Section: Resultsmentioning

confidence: 97%

A Pilot Study of Dose-Dense Paclitaxel With Trastuzumab and Lapatinib for Node-negative HER2-Overexpressed Breast Cancer

Iyengar

Fornier

Sugarman

et al. 2016

Clinical Breast Cancer

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Treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer with dual anti-HER2 therapy has been shown to improve outcomes. In the present pilot phase II study, patients with early-stage HER2-positive breast cancer received adjuvant treatment with dose-dense paclitaxel, trastuzumab, and lapatinib. However, this combination was not feasible because of unexpected toxicity. Background Dual anti-HER2 therapy is effective for HER2-amplified breast cancer. Weekly paclitaxel, trastuzumab, and full-dose lapatinib (PTL) is not feasible because of grade 3 diarrhea. We conducted a phase II feasibility study of dose-dense (DD; every other week) PTL (ClinicalTrials.gov identifier, NCT01827163). Patients and Methods Eligible patients had HER2-positive breast cancer, tumor size ≤ 3 cm, and negative nodes. Treatment included paclitaxel (175 mg/m2 × 4, every 2 weeks with pegfilgrastim), trastuzumab (4 mg/kg load and then 2 mg/kg weekly), and lapatinib (1000 mg daily). After paclitaxel × 4, trastuzumab (6 mg/kg every 3 weeks) plus lapatinib were continued for 1 year. The primary endpoint was feasibility, defined as (1) > 80% of patients completing PTL without a dose delay or reduction, (2) grade 3 diarrhea rate < 20%, and (3) cardiac event rate < 4%. Results From May 2013 to November 2013, we enrolled 20 of 55 planned patients. The median age was 49 years (range, 34–74 years). One patient had immediate paclitaxel hypersensitivity and was deemed inevaluable. Only 13 of 19 evaluable patients (68%) completed PTL without a dose delay or reduction or unacceptable toxicities. Only 3 of 19 (16%) had grade 3 diarrhea. Rash was frequent, with all grades in 18 of 19 (95%) and grade 3 in 2 of 19 (11%). The study was stopped early because of excess toxicity. Conclusion The discontinuation rate during DD PTL was high, owing, in part, to an unexpectedly high incidence of rash. The trial was halted, because the initial discontinuation rate from overall toxicity made it unlikely that full accrual would demonstrate feasibility.

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“…However, lapatinib can lead to serious drug-induced liver injury [24]. For example, a 60-year-old patient with metastatic breast cancer endured jaundice and increased serum aminotransferase levels after treatment with lapatinib for 14 days [25]. This liver injury is associated with the metabolic activity of lapatinib.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction Study Combining Lapatinib with Vorinostat in Rats

Lin

Wang²,

Zhou³

et al. 2015

Pharmacology

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Background: Because lapatinib and vorinostat [suberoylanilide hydroxamic acid (SAHA)] are both new anticancer drugs, interactions between SAHA and lapatinib remain unclear. This study examines pharmacokinetic interactions in simultaneous oral administration of SAHA and lapatinib to rats. Methods: Twenty-four rats were divided randomly into 3 groups: a lapatinib group (lapatinib 25 mg/kg, n = 8), a SAHA group (SAHA 25 mg/kg, n = 8), and a coadministration group (SAHA 25 mg/kg and lapatinib 25 mg/kg, n = 8). Using ultrahigh-performance liquid chromatography-tandem mass spectrometry, the concentrations of lapatinib and SAHA were determined in the plasma of the test rats. Results: Statistically significant pharmacokinetic differences appeared for lapatinib levels between the lapatinib and the coadministration group. When lapatinib was coadministered with SAHA, the AUC_0-t decreased from 39,816.6 to 23,712.8 ng/ml∙h (p < 0.05), while the mean residence time (MRT)_0-t increased from 7.0 to 10.3 h (p < 0.05) and t_1/2 increased from 3.5 to 6.4 h (p < 0.05). Between the SAHA levels for the SAHA group and those for the coadministration group, there appeared to be no statistically significant differences. Conclusion: The resulting data indicate that, when administered together, lapatinib does not influence the pharmacokinetic profile of SAHA in rats, while, in contrast, SAHA influences the pharmacokinetic profile of lapatinib.

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Lapatinib-induced hepatitis: A case report

Cited by 26 publications

References 11 publications

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

A Pilot Study of Dose-Dense Paclitaxel With Trastuzumab and Lapatinib for Node-negative HER2-Overexpressed Breast Cancer

Pharmacokinetic Interaction Study Combining Lapatinib with Vorinostat in Rats

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