Pharmacokinetics of amiloride after inhalation and oral administration in adolescents and adults with cystic fibrosis

Study Objective. To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF). Design. Open-label, randomized, two-way crossover, single-dose pharmacokinetic study. Setting. University hospital clinical research unit. Patients. Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > 50% predicted, Brasfield score ≥ 15). Interventions. Patients received amiloride solution orally (10 mg of amiloride l-mg/ml solution) and by inhalation [4.5 ml amiloride of l-mg/ml solution in 12% saline ( 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively. Measurements and Main Results. After oral dosing, the mean ± SD maximum peak concentration (C max ) was 20.6 ± 10.0 ng/ml at 3.2 ± 1.2 hours in adults and 21.7 ± 4.88 at 2.9 ± 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 ± 115 and 254 ± 60 ng.hr/ml in the adult and adolescent groups; half-life was 16.0 ± 0.7 and 13.4 ± 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (C max1 and C max2 ) with mean values of 1.57 ± 1.67 ng/ml at 0.5 ± 0.2 hours and 1.37 ± 1.21 ng/ml at 4.0 ± 1.0 hours for adults, and 1.49 ± 0.99 ng/ml at 0.5 ± 0.1 hours and 1.52 ± 0.81 ng/ml at 3.3 ± 0.5 hours for adolescents. Estimated mean ± SD dose nebulized was 1.91 ± 0.66 and 2.28 + 0.30 mg in the adult and adolescent groups, respectively. Mean ± SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 ± 17.6 and 15.4 ± 10.1 ng.hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group. Conclusions. Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier C max1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.