Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

Cancer Chemotherapy and Pharmacology
John F DeekenMichelle A Rudek

Abstract

Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib. Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC). Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold...Continue Reading

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Feb 4, 2014·Cancer Chemotherapy and Pharmacology·Michelle A RudekJohn F Deeken

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Citations

Dec 19, 2015·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J-P SpanoL Quéro
Jul 4, 2016·Pharmacological Reports : PR·Agnieszka KarbownikEdmund Grześkowiak
Jul 16, 2016·Biopharmaceutics & Drug Disposition·Ronilda D'CunhaGuohua An
Feb 25, 2018·The Journal of Pharmacology and Experimental Therapeutics·JoEllyn M McMillanLarisa Y Poluektova

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