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Related Experiment Video

Updated: Sep 20, 2025

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.

Carolina Säll1, Lene Alifrangis2, Kirsten Dahl2

  • 1Novo Nordisk A/S, Denmark cxls@novonordisk.com.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|June 9, 2022
PubMed
Summary

NN1177, a peptide drug, showed potential for drug-drug interactions in lab tests but not in clinical trials. This highlights the need for better preclinical models to predict interactions for peptide-based therapies.

Keywords:
Drug developmentPeptide hormonesclinical pharmacologycytochrome P450 regulationdrug-drug interactionshepatocytesin vitro-in vivo prediction (IVIVE)physiologically-based pharmacokinetic modeling/PBPK

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Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Clinical Pharmacology

Background:

  • NN1177 is a co-agonist of glucagon/glucagon-like peptide 1 receptors, developed for chronic weight management and non-alcoholic steatohepatitis.
  • Cytochrome P450 (CYP) enzymes are crucial for drug metabolism, and their inhibition or induction can lead to drug-drug interactions (DDIs).

Purpose of the Study:

  • To evaluate the in vitro effects of NN1177 on CYP enzyme expression and activity.
  • To assess the clinical relevance of in vitro findings by investigating DDIs between NN1177 and a cocktail of probe drugs in a Phase 1 clinical study.

Main Methods:

  • Freshly isolated human hepatocytes were treated with NN1177 to assess concentration-dependent effects on CYP enzymes.
  • A Phase 1 clinical study involved 45 participants receiving a cocktail of drugs (midazolam, caffeine, omeprazole, dextromethorphan, S-warfarin) alone and with NN1177.
  • Physiological-based pharmacokinetic modeling was used to simulate potential DDIs.

Main Results:

  • In vitro studies showed NN1177 caused concentration-dependent down-regulation of CYP3A4, CYP1A2, and CYP2B6 mRNA expression and activity.
  • Clinical trial results indicated no significant effect of NN1177 on the pharmacokinetics of midazolam or S-warfarin.
  • NN1177 co-administration led to decreased AUC(0-inf) and Cmax for omeprazole, caffeine, and dextromethorphan, but these changes did not align with in vitro predictions.

Conclusions:

  • Standard in vitro systems may not accurately predict drug-drug interaction risks for peptide-based drugs like NN1177.
  • The clinical outcomes suggest that the in vitro observed CYP down-regulation by NN1177 does not translate to clinically significant DDIs.
  • There is a critical need for improved preclinical models to better assess DDI potential for therapeutic peptides during drug development.