Population Pharmacokinetics of Intranasal Amiloride in Healthy Volunteers

Amiloride, an acid-sensing ion channel (ASIC) blocking agent with demonstrated anti-panic effects in preclinical models, is a promising candidate for rapid treatment of panic attacks. Intranasal administration enables rapid systemic uptake, and single-dose pharmacokinetics (PK) of intranasal amiloride in healthy adults have been described, but its population PK (PopPK) properties, including variability and absorption pathways, remain undefined. This study aimed to develop a PopPK model in healthy adults to characterize intranasal amiloride absorption kinetics and systemic exposure.

Healthy volunteers (n = 15) randomized equally to three dose groups (n = 5 per group) received 0.2, 0.4, or 0.6 mg intranasal amiloride via a mucosal atomization device, and plasma samples were collected over 24 h. PopPK modelling was performed in NONMEM^® using first-order conditional estimation. Structural models, covariates, variability, and residual error were evaluated with goodness-of-fit plots and prediction-corrected visual predictive checks. Simulations explored systemic exposure across 10-80 mg doses.

A first-order parallel dual absorption model with rapid nasal uptake and a slower secondary route via a transit compartment, combined with two-compartment disposition, best described the data. Key parameter estimates included a slow absorption rate constant of 0.136 h^-1, an apparent clearance of 19 L/h and apparent central volume of distribution of 9.83 L, and a nasal bioavailability fraction of 0.133.

Intranasal amiloride pharmacokinetics are best described by a dual-pathway absorption model with rapid and delayed uptake. This PopPK model provides a quantitative foundation for dose selection and further clinical development as a rapid-acting treatment for panic attacks.