Pediatric Acceptable Formulation of Amiodarone

描述（由申请人提供）：静脉胺碘酮是危及生命的室性心律失常和室上性心律失常的一线治疗。然而，由于低血压和心肌收缩抑制，Tween 80和苯甲醇稀释剂严重限制了给药率。这些不良毒性导致心脏骤停患者的高死亡率，这些患者由于长时间缺氧而有明显的心肌抑制。在醋酸缓冲溶液的新配方，pH 3.8已开发允许给药胺碘酮。然而，当外周静脉给药时，新的制剂引起明显更多的静脉炎。目前正在研究一种在pH值为6.8的醋酸缓冲液中重新配制胺碘酮的方法。该配方不会具有苯甲醇引起的儿科毒性，在临床研究中，苯甲醇导致儿科患者死亡，从而停止了进一步的临床试验，以获得胺碘酮的儿科适应症。此外，新的，中性pH制剂应减少低血压和静脉炎引起的所有目前的胺碘酮制剂。本基金提出的研究旨在确定具有更中性pH值的胺碘酮的新制剂的抗心律失常功效，降低低血压和减少静脉炎。公共卫生相关性：静脉注射胺碘酮是目前最有效的心脏紧急抗心律失常药物。它是ACLS指南推荐的心脏骤停患者的一线急救治疗。目前的配方含有Tween 80和苯甲醇，可导致低血压、肌萎缩阴性和儿科毒性（静脉炎和死亡）。API已经开发了一种胺碘酮醋酸缓冲液的配方，pH值为3.8，但当给药到外周静脉时，会导致更高的静脉炎发生率。静脉炎限制了该制剂的儿科效用。此外，苯甲醇对新生儿、婴儿和幼儿可能是致命的。静脉注射胺碘酮制剂的重新配方产生了一个稳定的产品，pH值为6.8，不含任何潜在的有毒稀释剂。本项目拟开展的研究旨在评估新制剂治疗静脉炎、低血压和抗心律失常的动物效果；为儿科人群开发可行产品的必要步骤。在成功完成临床前研究后，需要进行成人生物等效性研究，以获得FDA基于特殊方案评估的批准。

DESCRIPTION (provided by applicant): 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.