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Research ArticleArticle

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

Venkateswaran C. Pillai, Raman Venkataramanan, Robert A. Parise, Susan M. Christner, Roberto Gramignoli, Stephen C. Strom, Michelle A. Rudek and Jan H. Beumer
Drug Metabolism and Disposition October 2013, 41 (10) 1843-1851; DOI: https://doi.org/10.1124/dmd.113.052100
Venkateswaran C. Pillai
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Raman Venkataramanan
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Robert A. Parise
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Susan M. Christner
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Roberto Gramignoli
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Stephen C. Strom
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Michelle A. Rudek
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Jan H. Beumer
Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.)
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Abstract

Erlotinib is approved for the treatment of non–small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 μM)], ketoconazole (10 μM), efavirenz (10 μM), or rifampin (10 μM) for 4 days. On day 5, erlotinib (5 μM) was incubated with the above agents for another 24–48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t1/2) of erlotinib increased from 10.6 ± 2.6 to 153 ± 80 and 23.9 ± 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (CLint, app) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t1/2 of erlotinib from 10.3 ± 1.1 to 5.0 ± 1.5 and 3.4 ± 0.2 hours, respectively. Efavirenz and rifampin increased the CLint, app of erlotinib by 2.2- and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.

Footnotes

    • Received April 1, 2013.
    • Accepted August 1, 2013.
  • This work was supported by the National Institutes of Health National Cancer Institute [Grant P30-CA-047904].

  • dx.doi.org/10.1124/dmd.113.052100.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (10)
Drug Metabolism and Disposition
Vol. 41, Issue 10
1 Oct 2013
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Research ArticleArticle

Assessment of HIV-Anticancer Drug Interactions

Venkateswaran C. Pillai, Raman Venkataramanan, Robert A. Parise, Susan M. Christner, Roberto Gramignoli, Stephen C. Strom, Michelle A. Rudek and Jan H. Beumer
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1843-1851; DOI: https://doi.org/10.1124/dmd.113.052100

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Research ArticleArticle

Assessment of HIV-Anticancer Drug Interactions

Venkateswaran C. Pillai, Raman Venkataramanan, Robert A. Parise, Susan M. Christner, Roberto Gramignoli, Stephen C. Strom, Michelle A. Rudek and Jan H. Beumer
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1843-1851; DOI: https://doi.org/10.1124/dmd.113.052100
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