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Research ArticleArticle

In Vitro CYP450 Enzyme Downregulation by GLP-1/Glucagon Coagonist Does Not Translate to Observed Drug-Drug Interactions in the Clinic

Carolina Säll, Lene Alifrangis, Kirsten Dahl, Martin Haljeta Friedrichsen, Sune Boris Nygård and Kim Kristensen
Drug Metabolism and Disposition August 2022, 50 (8) 1087-1097; DOI: https://doi.org/10.1124/dmd.122.000865
Carolina Säll
Development ADME, Novo Nordisk A/S, Måløv, Denmark (C.S.); Discovery & Development PKPD, Novo Nordisk A/S, Måløv, Denmark (L.A., K.K.); Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark (K.D., M.H.F.); Early Clinical Pharmacology, Novo Nordisk A/S, Måløv, Denmark (K.D.); Global Development, Medical & Science Obesity and Metabolism, Novo Nordisk A/S, Søborg, Denmark (S.B.N.); and Translational Development, Precision Medicine, Novo Nordisk A/S, Måløv, Denmark (S.B.N.)
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Lene Alifrangis
Development ADME, Novo Nordisk A/S, Måløv, Denmark (C.S.); Discovery & Development PKPD, Novo Nordisk A/S, Måløv, Denmark (L.A., K.K.); Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark (K.D., M.H.F.); Early Clinical Pharmacology, Novo Nordisk A/S, Måløv, Denmark (K.D.); Global Development, Medical & Science Obesity and Metabolism, Novo Nordisk A/S, Søborg, Denmark (S.B.N.); and Translational Development, Precision Medicine, Novo Nordisk A/S, Måløv, Denmark (S.B.N.)
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Kirsten Dahl
Development ADME, Novo Nordisk A/S, Måløv, Denmark (C.S.); Discovery & Development PKPD, Novo Nordisk A/S, Måløv, Denmark (L.A., K.K.); Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark (K.D., M.H.F.); Early Clinical Pharmacology, Novo Nordisk A/S, Måløv, Denmark (K.D.); Global Development, Medical & Science Obesity and Metabolism, Novo Nordisk A/S, Søborg, Denmark (S.B.N.); and Translational Development, Precision Medicine, Novo Nordisk A/S, Måløv, Denmark (S.B.N.)
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Martin Haljeta Friedrichsen
Development ADME, Novo Nordisk A/S, Måløv, Denmark (C.S.); Discovery & Development PKPD, Novo Nordisk A/S, Måløv, Denmark (L.A., K.K.); Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark (K.D., M.H.F.); Early Clinical Pharmacology, Novo Nordisk A/S, Måløv, Denmark (K.D.); Global Development, Medical & Science Obesity and Metabolism, Novo Nordisk A/S, Søborg, Denmark (S.B.N.); and Translational Development, Precision Medicine, Novo Nordisk A/S, Måløv, Denmark (S.B.N.)
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Sune Boris Nygård
Development ADME, Novo Nordisk A/S, Måløv, Denmark (C.S.); Discovery & Development PKPD, Novo Nordisk A/S, Måløv, Denmark (L.A., K.K.); Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark (K.D., M.H.F.); Early Clinical Pharmacology, Novo Nordisk A/S, Måløv, Denmark (K.D.); Global Development, Medical & Science Obesity and Metabolism, Novo Nordisk A/S, Søborg, Denmark (S.B.N.); and Translational Development, Precision Medicine, Novo Nordisk A/S, Måløv, Denmark (S.B.N.)
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Kim Kristensen
Development ADME, Novo Nordisk A/S, Måløv, Denmark (C.S.); Discovery & Development PKPD, Novo Nordisk A/S, Måløv, Denmark (L.A., K.K.); Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark (K.D., M.H.F.); Early Clinical Pharmacology, Novo Nordisk A/S, Måløv, Denmark (K.D.); Global Development, Medical & Science Obesity and Metabolism, Novo Nordisk A/S, Søborg, Denmark (S.B.N.); and Translational Development, Precision Medicine, Novo Nordisk A/S, Måløv, Denmark (S.B.N.)
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Abstract

NN1177 is a glucagon/glucagon-like peptide 1 receptor coagonist investigated for chronic weight management and treatment of nonalcoholic steatohepatitis. Here, we show concentration-dependent downregulation of cytochrome P450 (P450) enzymes using freshly isolated human hepatocytes treated with this linear 29-amino acid peptide. Notably, reductions in CYP3A4 mRNA expression (57.2%–71.7%) and activity (18.5%–51.5%) were observed with a clinically relevant concentration of 100 nM NN1177. CYP1A2 and CYP2B6 were also affected but to a lesser extent. Physiologic-based pharmacokinetic modeling simulated effects on CYP3A4 and CYP1A2 probe substrates (midazolam and caffeine, respectively) and revealed potential safety concerns related to drug-drug interactions (DDIs). To investigate the clinical relevance of observed in vitro P450 downregulation, a phase 1 clinical cocktail study was initiated to assess the DDI potential. The study enrolled 45 study participants (body mass index 23.0–29.9 kg/m2) to receive a DDI cocktail (midazolam, caffeine, omeprazole, dextromethorphan, and S-warfarin/vitamin K) alone and following steady-state NN1177 exposure. The analysis of pharmacokinetic profiles for the cocktail drugs showed no significant effect from the coadministration of NN1177 on AUC0-inf for midazolam or S-warfarin. Omeprazole, caffeine, and dextromethorphan generally displayed decreases in AUC0-inf and Cmax following NN1177 coadministration. Thus, the in vitro observations were not reflected in the clinic. These findings highlight remaining challenges associated with standard in vitro systems used to predict DDIs for peptide-based drugs as well as the complexity of DDI trial design for these modalities. Overall, there is an urgent need for better preclinical models to assess potential drug-drug interaction risks associated with therapeutic peptides during drug development.

SIGNIFICANCE STATEMENT This study highlights significant challenges associated with assessing drug-drug interaction risks for therapeutic peptides using in vitro systems since potential concerns identified by standard assays did not translate to the clinical setting. Further research is required to guide investigators involved in peptide-based drug development towards better preclinical models in order to more accurately evaluate potential drug-drug interactions.

Footnotes

    • Received February 8, 2022.
    • Accepted May 5, 2022.
  • The study was funded by Novo Nordisk A/S.

  • The sponsor was involved in the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. C.S., L.A., K.D., M.H.F., S.B.N., and K.K. are employees at Novo Nordisk A/S. L.A., M.H.F., K.K., and K.D. own shares in Novo Nordisk A/S.

  • https://dx.doi.org/10.1124/dmd.122.000865.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (8)
Drug Metabolism and Disposition
Vol. 50, Issue 8
1 Aug 2022
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Research ArticleArticle

In Vitro P450 Suppression by Peptide Not Observed in Clinic

Carolina Säll, Lene Alifrangis, Kirsten Dahl, Martin Haljeta Friedrichsen, Sune Boris Nygård and Kim Kristensen
Drug Metabolism and Disposition August 1, 2022, 50 (8) 1087-1097; DOI: https://doi.org/10.1124/dmd.122.000865

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Research ArticleArticle

In Vitro P450 Suppression by Peptide Not Observed in Clinic

Carolina Säll, Lene Alifrangis, Kirsten Dahl, Martin Haljeta Friedrichsen, Sune Boris Nygård and Kim Kristensen
Drug Metabolism and Disposition August 1, 2022, 50 (8) 1087-1097; DOI: https://doi.org/10.1124/dmd.122.000865
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