Amélie Moreau1, Marc Le Vée2, Elodie Jouan2, Claire Denizot1, Yannick Parmentier1, Olivier Fardel3,4. 1. Centre de Recherche en Pharmacocinétique, Technologie Servier, Orléans, France. 2. Institut de Recherches en Santé, Environnement et Travail (IRSET) UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 34043, Rennes, France. 3. Institut de Recherches en Santé, Environnement et Travail (IRSET) UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 34043, Rennes, France. olivier.fardel@univ-rennes1.fr. 4. Pôle Biologie, Centre Hospitalier Universitaire, Rennes, France. olivier.fardel@univ-rennes1.fr.
Abstract
BACKGROUND AND OBJECTIVES: Gevokizumab is a potent anti-interleukin (IL)-1β neutralizing monoclonal antibody (mAb), which may be used for treating inflammatory or autoimmune diseases. The present study was designed to characterize the potential effects of this mAb towards well-established IL-1β-mediated repression of hepatic drug detoxifying proteins, like cytochrome P450 (CYP) 3A4 and drug transporters. METHODS: Primary cultured human hepatocytes were exposed to various concentrations of IL-1β in the absence or presence of gevokizumab (5 µg/mL); mRNA expression and activity of CYP3A4 and transporters were next determined. RESULTS: Gevokizumab was found to down-modulate, but not abolish, the repression of CYP3A4 and drug transporter mRNAs caused by IL-1β in human hepatocytes, through shifting up IL-1β half maximal inhibitory concentration (IC50) values by factors ranging from 6.8 to 10.4. The mAb concomitantly shifted IL-1β IC50 values towards CYP3A4 activity from 22.0 pg/mL (in the absence of gevokizumab) to 796 pg/mL (in the presence of gevokizumab) and counteracted the decrease of organic anion-transporting polypeptide activity occurring in response to 50 pg/mL IL-1β, but not that occurring at higher IL-1β concentration (1000 pg/mL). CONCLUSION: Gevokizumab attenuates, but not abolishes, IL-1β-mediated functional repression of CYP3A4 and drug transporters in human hepatocytes, which agrees with the fact that the mAb is considered as a modulator and not a blocker of IL-1β signaling. This attenuation of IL-1β-mediated down-regulation of hepatic detoxifying proteins by gevokizumab may have to be evaluated in terms of potential therapeutic protein drug-drug interactions when considering future development and therapeutic uses of this IL-1β neutralizing mAb.
BACKGROUND AND OBJECTIVES:Gevokizumab is a potent anti-interleukin (IL)-1β neutralizing monoclonal antibody (mAb), which may be used for treating inflammatory or autoimmune diseases. The present study was designed to characterize the potential effects of this mAb towards well-established IL-1β-mediated repression of hepatic drug detoxifying proteins, like cytochrome P450 (CYP) 3A4 and drug transporters. METHODS: Primary cultured human hepatocytes were exposed to various concentrations of IL-1β in the absence or presence of gevokizumab (5 µg/mL); mRNA expression and activity of CYP3A4 and transporters were next determined. RESULTS:Gevokizumab was found to down-modulate, but not abolish, the repression of CYP3A4 and drug transporter mRNAs caused by IL-1β in human hepatocytes, through shifting up IL-1β half maximal inhibitory concentration (IC50) values by factors ranging from 6.8 to 10.4. The mAb concomitantly shifted IL-1β IC50 values towards CYP3A4 activity from 22.0 pg/mL (in the absence of gevokizumab) to 796 pg/mL (in the presence of gevokizumab) and counteracted the decrease of organic anion-transporting polypeptide activity occurring in response to 50 pg/mL IL-1β, but not that occurring at higher IL-1β concentration (1000 pg/mL). CONCLUSION:Gevokizumab attenuates, but not abolishes, IL-1β-mediated functional repression of CYP3A4 and drug transporters in human hepatocytes, which agrees with the fact that the mAb is considered as a modulator and not a blocker of IL-1β signaling. This attenuation of IL-1β-mediated down-regulation of hepatic detoxifying proteins by gevokizumab may have to be evaluated in terms of potential therapeutic protein drug-drug interactions when considering future development and therapeutic uses of this IL-1β neutralizing mAb.
Entities:
Keywords:
Denosumab; Drug Transporter; Human Hepatocyte; Probenecid; Tocilizumab
Authors: Alexander M Owyang; Hassan Issafras; John Corbin; Kiran Ahluwalia; Paul Larsen; Elizabeth Pongo; Masahisa Handa; Arnold H Horwitz; Marina K Roell; Mary Haak-Frendscho; Linda Masat Journal: MAbs Date: 2011-01-01 Impact factor: 5.857
Authors: Theresa V Nguyen; Okechukwu Ukairo; Salman R Khetani; Michael McVay; Chitra Kanchagar; Wolfgang Seghezzi; Gulesi Ayanoglu; Onyi Irrechukwu; Raymond Evers Journal: Drug Metab Dispos Date: 2015-03-04 Impact factor: 3.922