Preliminary in vitro assessment of pharmacokinetic drug-drug interactions of EST64401 and EST64514, two sigma-1 receptor antagonists

Abstract

1. EST64401 and EST64514 are two selective sigma-1 receptor ligands that showed a good profile in a lead optimization process for oral pain treatment. Their potential for pharmacokinetic-based drug-drug interactions was assessed to anticipate clinical interactions.

2. Both compounds showed a low potential for CYP inhibition with percentages of inhibition <50% at 1 µM in recombinant human CYPs (CYP1A2, 2C9, 2C19, 2D6 and 3A4) and IC₅₀ ≥75 µM for CYP3A4 and 2D6 in human liver microsomes.

3. No CYP induction was observed for CYP1A2, 2B6 and 3A4 at concentrations ≤25 µM (EST64401) or ≤50 µM (EST64514) in human hepatocytes using as endpoints CYP activities and mRNA levels.

4. More than one enzyme participated in compound metabolism. The main enzymes involved were CYP3A4 for EST64401 and CYP2D6 besides CYP3A4 for EST64514.

5. Neither EST64401 nor EST64514 seemed to be substrates of P-gp or BCRP in Caco-2 cells (efflux ratio ≤2). Transporter inhibition was observed at concentrations ≥20 µM; EST64401 only inhibiting P-gp at higher concentrations (≥125 µM).

6. Preliminary in vitro interaction studies suggest a similar profile for EST64401 and EST64514. Therefore, other properties will have to be considered for compound differentiation and selection for further development.

Keywords:

• CYP inhibition
• CYP induction
• reaction phenotyping
• P-gp interaction
• BCRP interaction

Acknowledgements

The authors thank Drug Discovery & Development scientists of Esteve Pharmaceuticals for synthesizing the test compounds and helpful discussions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

These studies were part of the R&D project [IDI20150914], which was financially supported by the Spanish Ministerio de Economía y Competitividad (MINECO) through the Centro para el Desarrollo Tecnológico Industrial (CDTI), co-financed by the European Union through the European Regional Development Fund (ERDF).