Novel intranasal treatment for anxiety disorders using amiloride, an acid-sensing ion channel antagonist: Pharmacokinetic modeling and simulation.
Int J Clin Pharmacol Ther
; 60(6): 253-263, 2022 Jun.
Article
em En
| MEDLINE
| ID: mdl-35445658
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 ANDMETHODS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transtornos de Ansiedade
/
Bloqueadores do Canal Iônico Sensível a Ácido
/
Amilorida
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Int J Clin Pharmacol Ther
Assunto da revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Ano de publicação:
2022
Tipo de documento:
Article