Background and Objective <p>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.</p> Methods <p>Healthy volunteers (<i>n</i> = 15) randomized equally to three dose groups (<i>n</i> = 5 per group) received 0.2, 0.4, or 0.6&#xa0;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&#xa0;mg doses.</p> Results <p>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&#xa0;h⁻¹, an apparent clearance of 19&#xa0;L/h and apparent central volume of distribution of 9.83&#xa0;L, and a nasal bioavailability fraction of 0.133.</p> Conclusions <p>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.</p>