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

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Abstract

Purpose

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.

Methods

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).

Results

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 decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure.

Conclusion

CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.

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Acknowledgments

This work is funded by contract N02-CM-62212. The project described was supported by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH Grants P30 CA006973 and UL1 TR 001079, and Shared Instrument Grant 1S10RR026824-01) and Cancer Pharmacokinetics and Pharmacodynamics Facility at University of Pittsburgh Cancer Institute (P30 CA047904). Grant Number UL1 TR 001079 is from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS, or NIH.

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Author notes

  1. John F. Deeken

    Present address: INOVA Comprehensive Cancer and Research Institute, Virginia Commonwealth University, INOVA Campus, Falls Church, VA, USA

Authors and Affiliations

  1. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    John F. Deeken & Milan Rusnak

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Jan H. Beumer

  3. Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Jan H. Beumer

  4. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Jan H. Beumer

  5. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Bunting-Blaustein Cancer Research Bldg. Room 1M52, Baltimore, MD, 21231-1000, USA

    Nicole M. Anders, Teresia Wanjiku & Michelle A. Rudek

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  1. John F. Deeken
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Correspondence to Michelle A. Rudek.

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Deeken, J.F., Beumer, J.H., Anders, N.M. et al. Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib. Cancer Chemother Pharmacol 76, 813–819 (2015). https://doi.org/10.1007/s00280-015-2856-y

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  • DOI: https://doi.org/10.1007/s00280-015-2856-y

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