Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug-Drug Interactions

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  • Yeste Sandra
    Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D
  • Reinoso Raquel F.
    Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D
  • Ayet Eva
    Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D
  • Pretel Maria José
    Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D
  • Balada Ariadna
    Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D
  • Serafini Maria Teresa
    Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D

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  • Preliminary <i>in Vitro</i> Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug–Drug Interactions

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<p>EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug–drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. EST64454 showed a low potential for CYP inhibition (IC50 between 100 and 1000 µM) and as time-dependent inhibitor (IC50 shift mainly around 1). CYP induction studies with HepaRG™ cells revealed no CYP induction at concentrations ≤50 µM, as shown by the CYP1A2, 3A4 and 2B6 activities measured. Reaction phenotyping was assessed after incubation with recombinant human enzymes. Although a very low metabolism was observed, several enzymes catalyzed the formation of metabolites, including CYP3A4, 2C19 and flavin monooxygenases (FMO) 1 and 3. EST64454 was not a P-glycoprotein (P-gp) substrate and was highly permeable in Caco-2 cells. P-gp inhibition was only observed at 200 µM, the highest concentration studied. Preliminary studies suggest that neither CYP nor P-gp interaction of EST64454 would be of any concern for further development. At later stages, the interaction kinetics and the clinical relevance of these findings will be thoroughly evaluated.</p>

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