Michael D Schwartz1, Robert Raulli2, Judith W Laney2, William Coley2, Robert Walker2, Anna W O'Rourke2, Kathryn Raine2, Gary Horwith2, Yonghong Gao2, Derek L Eisnor2, Di Lu2, Brenda Wolling2, Gloria David3, Keli Johnson3, William T Barry3, Jamie Chang3, Brett Jepson3, Melanie Fein4. 1. Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), 200 C St., SW, Washington, DC, 20024, USA. Michael.schwartz@hhs.gov. 2. Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), 200 C St., SW, Washington, DC, 20024, USA. 3. Rho Federal Systems Division, Inc., 2635 E NC Highway 54, Durham, NC, 27713-2230, USA. 4. High Point Clinical Trials Center, 4160 Mendenhall Oaks Pkwy #105, High Point, NC, 27265, USA.
Abstract
INTRODUCTION: Atropine sulfate is an FDA-approved medical countermeasure (MCM) for the treatment of organophosphorus nerve agent and organophosphate pesticide toxicity. Sufficient MCM supplies must be available in an incident involving a mass human exposure either from an accidental chemical release or a terrorist attack. METHODS: We performed a randomized, 3-sequence, 3-period phase I crossover study to assess the bioavailability and pharmacokinetics (PK) of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic atropine sulfate solution administered sublingually to 15 healthy adult volunteers. The primary endpoint was evaluation of the bioavailability of each of the two sublingual doses against a 1.0 mg reference intravenous (IV) atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of atropine sulfate administered sublingually. RESULTS: Sublingual atropine was safe (no severe AEs or SAEs were reported with either dose) and well tolerated, with a single subject reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 493.81, and 816.47 min*ng/mL for the 0.5 mg and 1.0 mg sublingual doses, and the 1.0 mg IV dose, respectively. Compared to IV administration, the 1.0 mg sublingual dose produced 0.60 (90% CI: 0.55-0.66) of the overall concentration of atropine over time (AUC∞). CONCLUSION: Sublingual atropine sulfate 1% ophthalmic solution may be an alternative formulation and route of administration combination which expands the capacity and dosing options of atropine as a nerve agent MCM.
INTRODUCTION: Atropine sulfate is an FDA-approved medical countermeasure (MCM) for the treatment of organophosphorus nerve agent and organophosphate pesticide toxicity. Sufficient MCM supplies must be available in an incident involving a mass human exposure either from an accidental chemical release or a terrorist attack. METHODS: We performed a randomized, 3-sequence, 3-period phase I crossover study to assess the bioavailability and pharmacokinetics (PK) of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic atropine sulfate solution administered sublingually to 15 healthy adult volunteers. The primary endpoint was evaluation of the bioavailability of each of the two sublingual doses against a 1.0 mg reference intravenous (IV) atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of atropine sulfate administered sublingually. RESULTS: Sublingual atropine was safe (no severe AEs or SAEs were reported with either dose) and well tolerated, with a single subject reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 493.81, and 816.47 min*ng/mL for the 0.5 mg and 1.0 mg sublingual doses, and the 1.0 mg IV dose, respectively. Compared to IV administration, the 1.0 mg sublingual dose produced 0.60 (90% CI: 0.55-0.66) of the overall concentration of atropine over time (AUC∞). CONCLUSION: Sublingual atropine sulfate 1% ophthalmic solution may be an alternative formulation and route of administration combination which expands the capacity and dosing options of atropine as a nerve agent MCM.
Authors: Robert J Geller; Gaylord P Lopez; Stephen Cutler; Diana Lin; George F Bachman; Susan E Gorman Journal: Ann Emerg Med Date: 2003-04 Impact factor: 5.721