Novel intranasal treatment for anxiety disorders using amiloride, an acid-sensing ion channel antagonist: Pharmacokinetic modeling and simulation

Mahmoud Azzeh, Marco Battaglia, Simon Davies, John Strauss, Prashant Dogra, Venkata Yellepeddi

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: To develop a physiologically based pharmacokinetic (PBPK) model for amiloride, an acid-sensing ion channel (ASIC) antagonist, and to simulate its pharmacokinetics in plasma and the central nervous system following intranasal administration in a virtual human population.

MATERIALS AND METHODS: We first developed a PBPK model of amiloride after oral administration and optimized the model using data from five clinical studies. Next, we added a nasal compartment to the amiloride oral PBPK model and parameterized using data from previous clinical studies. We simulated amiloride's pharmacokinetics in plasma, brain, and cerebrospinal fluid (CSF) after intranasal administration of amiloride at various doses in a virtual human population.

RESULTS: The target amiloride concentration in the central nervous system required for maximal ASIC inhibition was achieved with a 75-mg intranasal amiloride dose. However, this finding is based on simulations performed using a mathematical model and needs to be further validated with appropriate clinical data.

CONCLUSION: The nasal PBPK model of amiloride could be used to design future clinical studies and allow for successful clinical translation of intranasal amiloride formulation.

Original languageEnglish (US)
Pages (from-to)253-263
Number of pages11
JournalInternational journal of clinical pharmacology and therapeutics
Volume60
Early online dateApr 21 2022
DOIs
StatePublished - Jun 2022

Keywords

  • Acid Sensing Ion Channel Blockers/administration & dosage
  • Acid Sensing Ion Channels/drug effects
  • Administration, Intranasal
  • Administration, Oral
  • Amiloride/administration & dosage
  • Anxiety Disorders/drug therapy
  • Computer Simulation
  • Humans
  • Models, Biological

ASJC Scopus subject areas

  • Medicine(all)

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