Comparative bioavailability of a premixed, ready-to-use formulation of intravenous amiodarone with traditional admixture in healthy subjects.

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 Premixed Injection is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight subjects were enrolled in this randomized, single-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 Premixed Injection and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The geometric ratio of the area under the concentration-time curve for time 0-72 hours (AUC0-72hr ) for amiodarone was 0.96 (95% confidence interval [CI], 0.94-0.99). The geometric ratio of the maximum concentration (Cmax ) for amiodarone was 0.87 (95% CI, 0.84-0.91). Because these ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to the PM101 Premixed Injection, ready-to-use formulation were identified.

Pharmacokinetics and platelet aggregation inhibitory effects of a novel intravenous formulation of clopidogrel in humans.

1. PM103 is an intravenous formulation of clopidogrel being developed as an alternative to oral clopidogrel to provide for dosing flexibility in the emergent clinical setting. The present first-in-human study assessed the pharmacokinetic and pharmacodynamic effects of PM103 and its safety in 144 healthy human subjects. 2. The present was a randomized open-label parallel-group trial. Single intravenous doses of PM103 (0.1, 1.0, 10, 30, 100 or 300 mg) were administered to each group (n = 24 subjects per group). Platelet aggregation was assessed at baseline and then 15 and 30 min and 2, 5 and 24 h after drug administration. Determination of plasma concentrations of clopidogrel, clopidogrel carboxylic acid metabolite and the clopidogrel thiol metabolite were assessed at baseline and at 1, 5, 10, 20 and 30 min and 1, 2, 3, 4, 6, 8, 12 and 24 h after drug administration. 3. PM103 produced a rapid, persistent and dose-related inhibition of platelet aggregation. The onset of the ant platelet effect paralleled the appearance in plasma of the clopidogrel thiol active metabolite. PM103 was well tolerated and no subjects discontinued treatment because of adverse events. 4. These data suggest that PM103 may be a suitable alternative to oral clopidogrel for patients in whom the desired clinical management would include administration of clopidogrel after coronary angiography but prior to percutaneous coronary intervention.

Reversal of heparin-induced increases in aPTT in the rat by PM102, a novel heparin antagonist.

Protamine is the only agent approved to reverse heparin-induced anticoagulation. Due to the significant adverse effects of protamine there is an important need for an alternative agent with an improved safety profile. The pharmacodynamics of PM102, a novel peptide-based heparin antagonist, was evaluated and compared to protamine in a rat model. Rats were dosed with intravenous heparin (50U/kg) and 4min later with protamine (0.25, 0.75mg/kg single intravenous bolus) or PM102 (0.1, 0.3, 1, 3, 30mg/kg single intravenous bolus). Blood samples were collected though 60min for assessment of activated partial thromboplastin time (aPTT) and plasma concentration of PM102. Both doses of protamine markedly lowered the elevated aPTT to baseline values within 1 to 5min after administration. PM102 (0.3-30mg/kg) also rapidly and completely reversed heparin-induced increases in aPTT within 1 to 5min. The effects of PM102 administered as an infusion over 10min also reversed aPTT with similar potency to that observed for bolus administration. The onset of reversal with infusion was delayed relative to the same total dose given as a bolus; however, the maximum effect was similar. PM102 rapidly (T(max) 1-2.6min) appeared in plasma after dosing. Concentrations of PM102 generally declined rapidly after reaching T(max) with a mean T(1/2) of 4 to 31min. PM102 is a novel synthetic peptide that effectively reverses the anticoagulant effect of heparin. It's utility as a bolus injection as well as infusion, its rapid efficacy and its rapid clearance make this an ideal candidate for clinical development.

PM101: intravenous amiodarone formulation changes can improve medication safety.

IMPORTANCE OF THE FIELD: Intravenous amiodarone (A-IV) is used to manage ventricular and atrial arrhythmias. The current formulation uses polysorbate 80 and benzyl alcohol to maintain amiodarone in solution, and these co-solvents are linked with clinically-important adverse events and pharmaceutical incompatibilities. PM101 is a recently FDA-approved intravenous formulation of amiodarone that uses a cyclodextrin to solubilize amiodarone. AREAS COVERED IN THIS REVIEW: This review describes the clinical and pharmaceutical development of formulations of amiodarone for intravenous administration. The medical and pharmaceutical literature was searched for papers discussing A-IV, PM101 and their formulation components. Relevant literature was identified starting from 1948 to the present. WHAT THE READER WILL GAIN: The reader will learn about the important medical and pharmaceutical issues complicating A-IV administration, including an understanding of related hypotension and compatibility with commonly used infusion materials and how these issues may impact drug safety. PM101 has been developed to address several of these important issues. TAKE HOME MESSAGE: PM101 is a new formulation of A-IV that is stable in commonly used infusion materials and avoids co-solvent related toxicities.

The hypotensive effect of intravenous amiodarone is sustained throughout the maintenance infusion period.

1. Hypotension frequently occurs with use of intravenous amiodarone and is managed by slowing the rate of administration. This response has been attributed to the cosolvents in the formulation and is believed to be solely related to the initial loading dose. The present study was performed to determine whether intravenous amiodarone-induced hypotension persists beyond the loading dose and into the maintenance infusion period and also whether hypotension occurs with maintenance level dosing alone. 2. Anaesthetized beagle dogs (n = 7/group) were instrumented to assess haemodynamics. Animals were treated with the human-equivalent dosing regimen (loading dose followed by maintenance infusion) of intravenous amiodarone or control (5% dextrose in water). 3. No haemodynamic changes were observed in the control group during the 6 h study. In contrast, administration of the standard intravenous amiodarone regimen produced rapid and significant decreases in mean aortic pressure, cardiac output and maximum rate of change of left ventricular pressure that persisted throughout the 6 h maintenance infusion period. Administration of amiodarone as the maintenance infusion dose alone produced haemodynamic changes that were similar in magnitude to those observed with administration of the full dosing regimen, but were delayed in onset by approximately 60 min. 4. Dosing with a cosolvent-free formulation of amiodarone (PM101) caused no haemodynamic effects during the 6 h dosing period, indicating that the cardiodepressant effects of intravenous amiodarone were due to its cosolvents. 5. These data suggest that consideration should be given to intravenous amiodarone as a potential cause for sustained hypotension during prolonged infusion.

Evaluation of the effects of PM101, a cyclodextrin-based formulation of intravenous amiodarone, on blood pressure in healthy humans.

Intravenous amiodarone (AIV) is used to treat cardiac arrhythmias. Hypotension is the dose-limiting adverse event of AIV and is considered to be due to the cosolvents (polysorbate 80 and benzyl alcohol) in the formulation. To minimize hypotension, the initial loading dose of AIV (150 mg) is diluted to 1.5 mg/ml and slowly infused over 10 minutes. PM101 is a cosolvent-free intravenous formulation of amiodarone. The present study was designed to assess any potential hypotensive effect of PM101 (50 mg/ml) on the administration of the loading dose (150 mg) as an undiluted bolus push. This was a randomized, double-blind, placebo- and active-controlled study in healthy human subjects receiving placebo (5% dextrose in water, n = 112) or PM101 (bolus push, n = 112). The primary end point was the noninferiority assessment of placebo versus PM101 for change in systolic blood pressure. For comparison, the standard loading dose of AIV (150 mg) was infused at 1.5 mg/ml over 10 minutes, and a rapid loading dose of AIV (150 mg) was infused undiluted (50 mg/ml) over 15 seconds. PM101 was noninferior to placebo, with changes from baseline systolic blood pressure for placebo and PM101 of -4.25 +/- 4.2 and -4.83 +/- 5.0 mm Hg, respectively. Neither regimen of AIV altered systolic blood pressure compared to placebo. Transient and significant increases in heart rate were observed in both AIV groups and with PM101 but not placebo. In conclusion, the results of this study demonstrate that PM101 is devoid of hypotension in healthy human subjects. The absence of a hypotensive effect of AIV in this population suggests that further evaluation is needed in a patient population with cardiac disease.

Comparison of the cardiac electrophysiology and general toxicology of two formulations of intravenous amiodarone in dogs.

Intravenous amiodarone (AIV) must be administered slowly after dilution to avoid hypotension, which is due to the cosolvents polysorbate 80 and benzyl alcohol used in its formulation. PM101 is a formulation of amiodarone devoid of these cosolvents, which enables bolus administration. We evaluated any potential toxicity or exaggerated adverse cardiac electrophysiologic effects of PM101 compared with AIV and control. Beagle dogs were treated with the human-equivalent amiodarone loading dose (2.14 mg/kg) with PM101 (bolus push) or AIV (10 min infusion in the toxicology study and bolus push in the electrophysiology study) followed by maintenance infusion (0.014 mg kg(-1) min(-1) through 6 h followed by 0.007 mg kg(-1) min(-1) through 14 days) or a control. General toxicology was assessed in conscious dogs over 14 days. Cardiac electrophysiology was assessed in a separate cohort of anesthetized dogs during the first 20 min of dosing. In the toxicology study, dosing in all animals in the AIV group was terminated within 17 min of initiation due to a severe hypersensitivity reaction. There were no acute adverse clinical signs in the PM101 or control groups. There were no significant effects on body weight or ECG parameters, and no adverse histomorphologic changes were seen in dogs that received PM101 or AIV. No significant exaggerated cardiac electrophysiologic effects of the approved doses PM101 or AIV were observed. PM101 may represent a formulation of intravenous amiodarone that could be administered rapidly without dilution in the setting of life-threatening cardiac arrhythmias.

PM101: a cyclodextrin-based intravenous formulation of amiodarone devoid of adverse hemodynamic effects.

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.

Bioequivalence of 2 intravenous amiodarone formulations in healthy participants.

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight participants were enrolled in this randomized, double-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The amiodarone plasma concentration-time curve observed with both formulations was virtually identical, as was the 72-hour area under the curve (AUC0-72). Similar equivalence was seen for desethylamiodarone, the active metabolite of amiodarone. The geometric ratios of the AUC0-72 for amiodarone and desethylamiodarone were 1.03 (95% confidence interval [CI], 1.00-1.06) and 1.01 (0.99-1.03), respectively. Similar geometric ratios and CIs were found for maximum plasma concentration (Cmax) and for AUC extrapolated to infinity (AUC0-infinity). Because the ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to PM101 were identified.