Hepatotoxicity Caused by Tyrosine Kinase Inhibitors
Lapatinib (Tykerb/Tyverb®, GlaxoSmithKline) is a dual inhibitor of the transmembrane receptor tyrosine kinase heterodimers HER2 and EGFR. Lapatinib is approved for oral use in patients with HER2-positive advanced or metastatic breast cancer in combination with other agents. In addition, clinical trials are ongoing to evaluate lapatinib in combination with trastuzumab in metastatic breast cancer, and also in adjuvant treatment of earlier stage breast cancer. Isolated ALT elevations (>3× ULN) have been observed in 3–5% of lapatinib-treated patients, isolated ALT elevations >5–20× ULN affect 1.6% and serious liver injury with hyperbilirubinemia occurs in 0.2%. Isolated bilirubin elevations affect 9% of lapatinib-treated breast cancer patients, are associated with the inconsequential Gilbert's syndrome and so are generally asymptomatic and reversible. Lapatinib prescribing information includes guidelines for liver chemistry monitoring and the clinical management of hepatotoxicity. An evaluation of physician compliance with liver chemistry monitoring during lapatinib treatment was performed using electronic medical records from a large US oncology database, and revealed good (>80%) compliance with liver chemistry monitoring following a liver safety labeling update.
Lapatinib undergoes extensive metabolism, predominantly by the CYP450 enzymes CYP3A4 and CYP3A5, to form a variety of metabolites. Lapatinib is a substrate and inhibitor of the transporter enzymes BCRP (ABCG2) and P-gp (ABCB1) and also an inhibitor of OATP1B1 (SLCO1B1) at clinically relevant concentrations. Recently, lapatinib metabolism and excretion in healthy human volunteers and laboratory animals has been further characterized, resulting in the identification of dealkylated phenolic metabolites of lapatinib potentially related to hepatotoxicity. The lapatinib dealkylated phenol metabolite is reported to be an inhibitor in vitro of BSEP and disruption of hepatocyte bile salt efflux has been reported as a cause for cholestatic liver damage. Furthermore, dogs receiving 7-day high-dose lapatinib treatment exhibited cholestatic liver injury and mass spectroscopic imaging of dog liver histological sections has shown colocalization of lapatinib oxidative metabolites in areas of hepatic inflammation and necrosis.
Lapatinib & DILI
Lapatinib (Tykerb/Tyverb®, GlaxoSmithKline) is a dual inhibitor of the transmembrane receptor tyrosine kinase heterodimers HER2 and EGFR. Lapatinib is approved for oral use in patients with HER2-positive advanced or metastatic breast cancer in combination with other agents. In addition, clinical trials are ongoing to evaluate lapatinib in combination with trastuzumab in metastatic breast cancer, and also in adjuvant treatment of earlier stage breast cancer. Isolated ALT elevations (>3× ULN) have been observed in 3–5% of lapatinib-treated patients, isolated ALT elevations >5–20× ULN affect 1.6% and serious liver injury with hyperbilirubinemia occurs in 0.2%. Isolated bilirubin elevations affect 9% of lapatinib-treated breast cancer patients, are associated with the inconsequential Gilbert's syndrome and so are generally asymptomatic and reversible. Lapatinib prescribing information includes guidelines for liver chemistry monitoring and the clinical management of hepatotoxicity. An evaluation of physician compliance with liver chemistry monitoring during lapatinib treatment was performed using electronic medical records from a large US oncology database, and revealed good (>80%) compliance with liver chemistry monitoring following a liver safety labeling update.
Lapatinib undergoes extensive metabolism, predominantly by the CYP450 enzymes CYP3A4 and CYP3A5, to form a variety of metabolites. Lapatinib is a substrate and inhibitor of the transporter enzymes BCRP (ABCG2) and P-gp (ABCB1) and also an inhibitor of OATP1B1 (SLCO1B1) at clinically relevant concentrations. Recently, lapatinib metabolism and excretion in healthy human volunteers and laboratory animals has been further characterized, resulting in the identification of dealkylated phenolic metabolites of lapatinib potentially related to hepatotoxicity. The lapatinib dealkylated phenol metabolite is reported to be an inhibitor in vitro of BSEP and disruption of hepatocyte bile salt efflux has been reported as a cause for cholestatic liver damage. Furthermore, dogs receiving 7-day high-dose lapatinib treatment exhibited cholestatic liver injury and mass spectroscopic imaging of dog liver histological sections has shown colocalization of lapatinib oxidative metabolites in areas of hepatic inflammation and necrosis.
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