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Abstract: PO2373

Evaluation of Veverimer Drug Interaction Potential

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Shao, Jun, Tricida, Inc., South San Francisco, California, United States
  • Parsell, Dawn, Tricida, Inc., South San Francisco, California, United States
  • Guttendorf, Robert, Aclairo Pharmaceutical Development Group, Vienna, Virginia, United States
  • Wu, Yick Sen, Tricida, Inc., South San Francisco, California, United States
  • Tsao, Lillian, Unaffiliated, Burlingame, California, United States
  • Tabakman, Scott, Tricida, Inc., South San Francisco, California, United States
  • Stasiv, Yuri, Tricida, Inc., South San Francisco, California, United States
  • Lee, Angela A., Tricida, Inc., South San Francisco, California, United States
  • Biyani, Kalpesh N., Tricida, Inc., South San Francisco, California, United States
  • Klaerner, Gerrit, Tricida, Inc., South San Francisco, California, United States
Background

Veverimer is an orally administered HCl binder for treatment of metabolic acidosis in CKD. We assessed its potential for drug-drug interactions (DDIs) using a strategy based on its physicochemical characteristics. Since veverimer is a non-absorbed polymer, potential DDIs are limited to effects on absorption of other oral drugs via (1) direct binding or (2) increases in gastric pH resulting from HCl binding.

Methods

Features important for binding to veverimer were determined in vitro. A set of anionic probes and a panel of 16 drugs were used to define characteristics required for binding. Test drugs covered a broad range of size, charge, solubility and permeability characteristics across 14 drug classes. The magnitude and duration of veverimer’s effect on gastric pH was determined in fed and fasting healthy subjects via 22-h monitoring with an intragastric pH probe. Results from binding and gastric pH studies informed selection of drugs for human DDI studies.

Results

In vitro studies showed the most important determinant for binding to veverimer is negative charge, with small size as a secondary determinant. Veverimer did not bind any positively charged, neutral or zwitterionic drugs. Negatively charged drugs >435 Da did not bind; the presence of chloride reduced or eliminated binding. The 2 drugs showing the most binding to veverimer in vitro (furosemide, aspirin) were chosen for human DDI studies.

Veverimer increased gastric pH by ~3.0 (fasted) and 1.5 (fed) pH units. The gastric pH increase was transient, peaking by 1 h after dosing and returning to baseline after 1.5 (fasting) and 3 (fed) hours. Based on these results, 2 drugs with pH-dependent solubility (warfarin, dabigatran) were chosen for human DDI studies. In human DDI studies, no clinically meaningful changes in bioavailability were observed for furosemide, aspirin, dabigatran, or warfarin when coadministered with veverimer.

Conclusion

We observed: 1) no effect of veverimer on the bioavailability of drugs most susceptible to binding to the polymer; 2) modest, transient effects of veverimer on gastric pH; 3) no effect on bioavailability of drugs with pH-sensitive solubility. We conclude that there is a negligible risk of clinically significant veverimer DDIs.

Funding

  • Commercial Support –