Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI

Clin Pharmacol Ther. 2020 Jan;107(1):269-277. doi: 10.1002/cpt.1599. Epub 2019 Sep 16.

Abstract

Mechanistic understanding of complex clinical drug-drug interactions (DDIs) with potential involvement of multiple elimination pathways has been challenging, especially given the general lack of specific probe substrates for transporters. Here, we conducted a clinical DDI study to evaluate the interaction potential of fenebrutinib using midazolam (MDZ; CYP3A), simvastatin (CYP3A and OATP1B), and rosuvastatin (BCRP and OATP1B) as probe substrates. Fenebrutinib (200 mg) increased the area under the curve (AUC) of these probe substrates twofold to threefold. To evaluate the mechanism of the observed DDIs, we measured the concentration of coproporphyrin I (CP-I) and coproporphyrin III (CP-III), endogenous biomarkers of OATP1B. There was no change in CP-I or CP-III levels with fenebrutinib, suggesting that the observed DDIs were caused by inhibition of CYP3A and BCRP rather than OATP1B, likely due to increased bioavailability. This is the first published account using an endogenous transporter biomarker to understand the mechanism of complex DDIs involving multiple elimination pathways.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Adult
  • Area Under Curve
  • Biomarkers / metabolism
  • Cytochrome P-450 CYP3A / drug effects*
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Interactions
  • Female
  • Humans
  • Liver-Specific Organic Anion Transporter 1 / drug effects
  • Liver-Specific Organic Anion Transporter 1 / metabolism
  • Male
  • Midazolam / pharmacokinetics
  • Middle Aged
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Piperazines / administration & dosage
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridones / administration & dosage
  • Pyridones / pharmacology*
  • Rosuvastatin Calcium / pharmacokinetics
  • Simvastatin / pharmacokinetics
  • Young Adult

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Biomarkers
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridones
  • SLCO1B1 protein, human
  • Rosuvastatin Calcium
  • Simvastatin
  • fenebrutinib
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Midazolam