title: PM101: a cyclodextrin-based intravenous formulation of amiodarone devoid of adverse hemodynamic effects.
abstract: Intravenous amiodarone (Amiodarone i.v.) is widely used to treat cardiac arrhythmias. The most frequent clinical adverse event associated with Amiodarone i.v. administration is systemic hypotension which has been attributed to the cosolvents used in the formulation, polysorbate 80 and benzyl alcohol. To minimize hypotension Amiodarone i.v. is diluted in 5% dextrose in water prior to administration and slowly infused. PM101 is a novel intravenous formulation that uses sulfobutylether-7-beta-cyclodextrin to solubilize amiodarone, and thus should be devoid of the untoward hemodynamic effects associated with polysorbate 80 and benzyl alcohol. Beagle dogs (n=7/group) were anesthetized with morphine and alpha-chloralose and instrumented to assess aortic blood pressure, cardiac output, cardiac contractility, and heart rate. Animals were treated with the U.S. approved human-equivalent loading dose (2.14 mg/kg) of Amiodarone i.v., PM101, and their respective vehicle controls. Administration of Amiodarone i.v. rapidly and significantly decreased mean aortic pressure, cardiac output, and cardiac contractility. A significant increase in heart rate was also observed as was a transient, but not significant, decrease in systemic vascular resistance. A similar pattern of rapid and significant hemodynamic changes was produced by the Amiodarone i.v. Vehicle (polysorbate 80/benzyl alcohol) alone. In marked contrast, PM101 and its vehicle produced no significant hemodynamic effects. This study provides a useful model for the continued search for a safe and effective intravenous amiodarone formulation devoid of the hypotensive risk associated with the current commercial formulation.
authors.affiliation: Prism Pharmaceuticals Inc., King of Prussia, Pennsylvania, United States. dcushing@prismpharma.com
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cushing
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kowey
authors.forename: Warren D
authors.initials: WD
authors.lastname: Cooper
authors.forename: Bill W
authors.initials: BW
authors.lastname: Massey
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gralinski
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Lipicky
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000009:adverse effects; D019905:Benzyl Alcohol / Q000009:adverse effects / Q000737:chemistry; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D005079:Excipients / Q000009:adverse effects / Q000737:chemistry; D005260:Female; D005947:Glucose / Q000009:adverse effects / Q000737:chemistry; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D009200:Myocardial Contraction / Q000187:drug effects; D011136:Polysorbates / Q000009:adverse effects / Q000737:chemistry; D012995:Solubility; D047392:beta-Cyclodextrins / Q000009:adverse effects / Q000737:chemistry*
chemical_list: D000889:Anti-Arrhythmia Agents; D005079:Excipients; D011136:Polysorbates; C103513:SBE7-beta-cyclodextrin; D047392:beta-Cyclodextrins; D005947:Glucose; D019905:Benzyl Alcohol; D000638:Amiodarone