Systemic Delivery of Atropine Sulfate by the MicroDose Dry-Powder Inhaler

Background: Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). Methods: The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses x 0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen (R) auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. Results: A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA = 20.1 +/- 5.8, AUTO=23.7 +/- 4.9 ng hr/mL (means +/- SD); maximum concentration reached, DPIA=7.7 +/- 3.5, AUTO=11.0 +/- 3.8 ng/mL; time to reach maximum concentration, DPIA=0.25 +/- 0.47, AUTO=0.19 +/- 0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18 +/- 12, AUTO=23 +/- 13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16 +/- 0.22 L, AUTO=0.11 +/- 0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. Conclusions: Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine.