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Contribution of Major Metabolites Towards Complex Drug-Drug Interactions of Deleobuvir: in Vitro Predictions and in Vivo Outcomes

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Contribution of Major Metabolites Towards Complex Drug-Drug Interactions of Deleobuvir: in Vitro Predictions and in Vivo Outcomes DMD Fast Forward. Published on December 18, 2015 as DOI: 10.1124/dmd.115.066985 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66985 Contribution of major metabolites towards complex drug-drug interactions of deleobuvir: in vitro predictions and in vivo outcomes Rucha S Sane, Diane Ramsden, John P Sabo, Curtis Cooper, Lois Rowland, Naitee Ting, Andrea Whitcher-Johnstone and Donald J Tweedie Downloaded from Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA (R.S.S, D.R., J.P.S., dmd.aspetjournals.org L.R., N.T., A.W.J, D.J.T) University of Ottawa, Canada (C.C.) at ASPET Journals on October 1, 2021 Page | 1 DMD Fast Forward. Published on December 18, 2015 as DOI: 10.1124/dmd.115.066985 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66985 RUNNING TITLE: CYP450 DDI of deleobuvir and its metabolites Please address correspondence to: Rucha S. Sane Translational Medicine and Clinical Pharmacology Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA. Downloaded from Phone: (203) 798-6549 dmd.aspetjournals.org Fax: (203) 837 4555 E-mail: [email protected] at ASPET Journals on October 1, 2021 Number of Text pages: 45 Tables: 6 Figures: 5 References: 48 Number of Words Abstract: 248 Introduction: 746 Discussion: 1,831 Page | 2 DMD Fast Forward. Published on December 18, 2015 as DOI: 10.1124/dmd.115.066985 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66985 Non standard Abbreviations: AUC, area under the concentration time curve; Cmax, maximum plasma concentration; CYP450, cytochromes P450; DDI, drug drug interaction; DMEs, drug metabolizing enzymes; Fa, fraction absorbed after oral administration;fu,p, free fraction of drug in plasma; HCV, hepatitis C virus; HIM, human intestinal microsomes; HLM, human liver microsomes; IC50, concentration which achieves a 50% inhibitory effect; ICM, induction culture media; ka, first order absorption rate constant; LC-MS/MS, high performance liquid chromatography-tandem mass spectrometry; Downloaded from Qen, blood flow through enterocytes; Qh, hepatic blood flow; r: recombinant; dmd.aspetjournals.org at ASPET Journals on October 1, 2021 Page | 3 DMD Fast Forward. Published on December 18, 2015 as DOI: 10.1124/dmd.115.066985 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66985 Abstract The drug-drug interaction (DDI) potential of deleobuvir, an HCV protease inhibitor, and its two major metabolites, CD 6168 (formed via reduction by gut bacteria) and deleobuvir-AG (acyl glucuronide), was assessed in vitro. AUC (AUCi/AUC) ratios were predicted using a static model and compared to actual AUC ratios for probe substrates in a CYP450 cocktail of caffeine (CYP1A2), tolbutamide (CYP2C9) and midazolam (CYP3A4), administered before and after 8 days of deleobuvir administration to HCV positive patients. In vitro studies assessed inhibition, Downloaded from inactivation and induction of CYP450s. Induction was assessed in a short incubation (10h) hepatocyte assay, validated using positive controls, to circumvent cytotoxicity seen with dmd.aspetjournals.org deleobuvir and its metabolites. Overall, CYP450 isoforms were differentially affected by deleobuvir and its two metabolites. Of note was more potent CYP2C8 inactivation by deleobuvir-AG than deleobuvir and CYP450 induction by CD 6168 but not by deleobuvir. The at ASPET Journals on October 1, 2021 predicted net AUC ratios for probe substrates were 2.92 (CYP1A2), 0.45 (CYP2C9), and 0.97 (CYP3A4) compared to clinically observed ratios of 1.64 (CYP1A2), 0.86 (CYP2C9 and 1.23 (CYP3A4). Predictions of DDI using deleobuvir alone would have significantly over predicted the DDI potential for CYP3A4 inhibition (AUC ratio of 6.15). Including metabolite data brought the predicted net effect close to the observed DDI. However, the static model over predicted the induction of CYP2C9 and inhibition/inactivation of CYP1A2. This multi-perpetrator DDI scenario highlights the application of the static model for predicting complex DDI for CYP3A4 and exemplifies the importance of including key metabolites in an overall DDI assessment. Page | 4 DMD Fast Forward. Published on December 18, 2015 as DOI: 10.1124/dmd.115.066985 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66985 Introduction Deleobuvir (BI 207127) is an inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase and in combination with faldaprevir and ribavirin, achieved high sustained viral load reduction in treatment-naïve and treatment-experienced patients with chronic genotype 1b infection (Zeuzem et al., 2013). In a disposition study in which 14C-deleobuvir was administered to healthy male human volunteers, two major metabolites of deleobuvir were identified, an alkene reduction product (CD 6168) formed by gut bacteria and deleobuvir-acyl glucuronide (deleobuvir-AG) Downloaded from (Figure 1) (Chen et al., 2015; McCabe et al., 2015). Following a single oral dose of 800 mg deleobuvir to healthy volunteers, CD 6168 and deleobuvir-AG exposure (AUC0-∞) in the dmd.aspetjournals.org systemic circulation were 27% and 43%, respectively, of the parent deleobuvir. Both CD 6168 and deleobuvir-AG are pharmacologically active against HCV viral replication, albeit 10- and 3- fold less potent, respectively, than deleobuvir (data on file at Boehringer Ingelheim). at ASPET Journals on October 1, 2021 According to the drug-drug interaction guidance documents from the FDA (FDA, 2012) and the EMA (EMA, 2012), contribution of major metabolites should be considered in assessing overall DDI liability of the parent compound if a metabolite concentration is >25% of the parent and/or if a metabolite concentration is >10% of total drug related material in circulation. Higher cut off values have been proposed in the literature based on the logic that polar metabolites lacking structural alerts are typically less potent CYP450 inhibitors and inactivators than the parent drug (Callegari et al., 2013; Yu and Tweedie, 2013; Yu et al., 2015). These approaches have largely focused on DDI as a result of inhibition and inactivation. Recent evaluations to estimate clinical drug-drug interaction risk involving a combination of inhibition, inactivation and induction, using dynamic PBPK models, as well as simpler static models, have shown promising results for CYP3A4 (Fahmi et al., 2008a; 2008b; Zhao et al., Page | 5 DMD Fast Forward. Published on December 18, 2015 as DOI: 10.1124/dmd.115.066985 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66985 2011; Einolf et al., 2014). In this study, in vitro DDI assessment was performed for parent drug, deleobuvir, and both of its major metabolites. In vitro, deleobuvir, CD 6168 and/or deleobuvir- AG affected activities of several CYP450 isoforms by competitive inhibition, inactivation and/or induction. Dynamic models incorporate temporal changes in drug and enzyme levels in a sophisticated manner, thereby minimizing over-prediction of interaction. Static models usually incorporate only the maximal plasma concentrations or the portal vein inlet concentrations which may not be realistic at all times during coadministration of interacting drugs. In the case of Downloaded from deleobuvir, the complexity of incorporating three perpetrator compounds, with mixed effects, made attempts at dynamic models very challenging and as such, a simpler static model, modified dmd.aspetjournals.org to incorporate multiple perpetrators, was used to evaluate the accuracy of prediction of the effect of deleobuvir on CYP1A2, CYP2C9 and CYP3A4 activity in vivo and then to predict the effect on other CYP450 isoforms as feasible. at ASPET Journals on October 1, 2021 An in vivo study was conducted in HCV positive patients to assess the net effect of deleobuvir (and generated metabolites) on the pharmacokinetics of caffeine, tolbutamide and midazolam, used in combination as an in vivo probe substrate cocktail for CYP1A2, CYP2C9 and CYP3A4 activities, respectively (Fuhr et al., 2007; Sabo et al., 2015). The patients in this study also received PEG-Interferon and ribavirin as part of the standard of care. Based on information in the Copegus® drug label, ribavirin is not expected to affect CYP450 enzymes. However, there are reports of PEG-interferon α-2b inhibiting CYP1A2, albeit very mildly. These studies assessed the effect of PEG-interferon α-2b after ~1 month of treatment (Gupta et al., 2011; Brennan et al., 2013) which is much longer than the duration reported for our study. Further, in a parallel arm to our study, PEG-Interferon α-2b and ribavirin were administered in an identical regimen in combination with faldaprevir and had no effect on CYP1A2 and CYP2C9 activities Page | 6 DMD Fast Forward. Published on December 18, 2015 as DOI: 10.1124/dmd.115.066985 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66985 (Sabo et al., 2015). As such, PEG-interferon α-2b was not expected to have an impact on CYP1A2 and the effects seen on the probe substrates are considered to be due to treatment with deleobuvir and its metabolites. The in vitro DDI predictions for CYP1A2, CYP2C9 and CYP3A4 for deleobuvir and its generated metabolites were compared to the clinical DDI
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