IV amiodarone is the first line therapy for life threatening ventricular as well as supraventricular arrhythmias. However, the Tween 80 and benzyl alcohol diluents limits the rate of administration severely, due to hypotension and myocardial contractile depression. These adverse toxicities contribute to the high mortality of cardiac arrest patients who have marked myocardial depression due to prolonged hypoxia. A new formulation in an acetate buffer solution, pH 3.8 has been developed permitting bolus administration of amiodarone. However, the new preparation causes significantly more phlebitis when administered by peripheral vein. A reformulated preparation of amiodarone not in an acetate buffer, at pH 6.8 is currently under study. The formulation will not possess the pediatric toxicity that the benzyl alcohol causes, that in clinical studies resulted in deaths in pediatric patients, halting further clinical trials to obtain a pediatric indication for amiodarone. Additionally the new, neutral pH formulation should reduce the hypotension and phlebitis caused by all current amiodarone formulations. Studies proposed in this grant aim to establish the anti-arrhythmic efficacy, the reduced hypotension and reduced phlebitis that the newer preparation of amiodarone with the more neutral pH offers.
Public Health Relevance: IV amiodarone is the most effective cardiac emergency anti-arrhythmic available. It is first line emergency therapy for cardiac arrest patients as recommended by ACLS guidelines. The current formulation has Tween 80 and benzyl alcohol that causes hypotension, negative inotrophy and pediatric toxicity (phlebitis and mortality). API has developed a formulation of amiodarone in an acetate buffer, pH 3.8 but this causes a higher incidence of phlebitis when administered into peripheral veins. The phlebitis limits the pediatric utility of the preparation. Additionally, benzyl alcohol may be fatal in the newborn, infant and small child. A reformulation of the IV amiodarone preparation has yielded a stable product at pH 6.8 that does not contain any potentially toxic diluent. The studies proposed in this grant aim to evaluate the new formulation for phlebitis, hypotension and anti-arrhythmic effectiveness in animals; requisite steps in the development of a viable product for the pediatric population. At the successful completion of the pre-clinical studies, a bioequivalence study in adults would be requisite for FDA approval based on a Special Protocol Assessment granted by FDA.
Public Health Relevance Statement: Project Narrative IV amiodarone is the most effective cardiac emergency anti-arrhythmic available. It is first line emergency therapy for cardiac arrest patients as recommended by ACLS guidelines. The current formulation has Tween 80 and benzyl alcohol that causes hypotension, negative inotrophy and pediatric toxicity (phlebitis and mortality). API has developed a formulation of amiodarone in an acetate buffer, pH 3.8 but this causes a higher incidence of phlebitis when administered into peripheral veins. The phlebitis limits the pediatric utility of the preparation. Additionally, benzyl alcohol may be fatal in the newborn, infant and small child. A reformulation of the IV amiodarone preparation has yielded a stable product at pH 6.8 that does not contain any potentially toxic diluent. The studies proposed in this grant aim to evaluate the new formulation for phlebitis, hypotension and anti-arrhythmic effectiveness in animals; requisite steps in the development of a viable product for the pediatric population. At the successful completion of the pre-clinical studies, a bioequivalence study in adults would be requisite for FDA approval based on a Special Protocol Assessment granted by FDA.
NIH Spending Category: Cardiovascular; Heart Disease; Hematology; Pediatric
Project Terms: 0-11 years old; 0-6 weeks old; 21+ years old; API; Acetates; Adult; Adverse effects; Agreement; Amiodarone; Anesthesia; Anesthesia procedures; Animals; Anti-Arrhythmia Agents; Anti-Arrhythmia Drugs; Anti-Arrhythmics; Antiarrhythmia Agents; Antiarrhythmia Drugs; Antiarrhythmic Drugs; Apoplexy; Asystole; Benzyl Alcohols; Bioequivalence; Blood Pressure; Blood Pressure, Low; Blood Vessels; Bolus; Bolus Infusion; Buffers; Canine Species; Canis familiaris; Cardiac; Cardiac Arrest; Cardiac Surgery; Cardiac Surgery procedures; Cardiac Surgical Procedures; Cause of Death; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Cessation of life; Child; Child Youth; Childhood; Children (0-21); Clinical Equivalency; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; Complication; Conscious; Consciousness; Death; Development; Dogs; Drug Formulations; Drugs; Ear; Ear structure; Effectiveness; Emergencies; Emergency Situation; Emergency treatment; Formulation; Formulations, Drug; Generic Equivalency; Grant; Guidelines; Heart Arrest; Human, Adult; Human, Child; Hypotension; Hypoxia; Hypoxic; Incidence; Infant, Newborn; Life; MAPI; Mammals, Dogs; Mammals, Rabbits; Mammals, Rats; Medication; Methanone, (2-butyl-3-benzofuranyl)(4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl)-; Modeling; Mortality; Mortality Vital Statistics; Myocardial; Myocardial depression; Myocardial dysfunction; Newborn Infant; Newborns; Oryctolagus cuniculus; Oxygen Deficiency; Patients; Peripheral; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phenylcarbinols; Phenylmethanols; Phlebitis; Population; Preparation; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; Rabbit, Domestic; Rabbits; Rat; Rattus; Secondary to; Solutions; Stroke; Supraventricular Arrhythmia; Surgical Procedures, Heart; Syndrome; System; System, LOINC Axis 4; Therapeutic Equivalency; Therapy, Emergency; Toxic effect; Toxicities; Treatment Side Effects; Tween 80; Vascular Accident, Brain; Vascular Hypotensive Disorder; Veins; Ventricular; Ventricular Tachycardia; adult human (21+); alkaline protease inhibitor; antiarrhythmic agent; aqueous; arrhythmic agent; base; brain attack; canine; cerebral vascular accident; children; clinical investigation; depression; domestic dog; drug bioequivalence; drug bioequivalent; drug/agent; falls; heart surgery; irritation; microbial alkaline proteinase inhibitor; newborn human (0-6 weeks); pediatric; preclinical study; premature; programs; public health relevance; side effect; stroke; therapy adverse effect; treatment adverse effect; vascular; youngster
