Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion.

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.

Is randomization to placebo safe? Risk in placebo-controlled angina trials: angina risk meta-analysis.

OBJECTIVE: It was the aim of this study to document the risks of symptomatic patients with angina in placebo-controlled, anti-anginal drug development trials in which symptom-limited exercise testing was used as the primary endpoint. PATIENTS AND METHODS: The original case report forms submitted to the United States Food and Drug Administration in support of approval of new or supplemental new drug applications between 1973 and 2001 were identified and subjected to a by-patient meta-analysis, utilizing both a maximum likelihood analysis and classical Mantel-Haenszel methods. RESULTS: There were 63 placebo-controlled, clinical trials that randomized 10,865 patients, with 1,047 patient-years of observation time. The trials involved 21 different chemical entities from 4 different drug classes. The relative risk (RR) for withdrawal (placebo compared to drug-treated patients) was not increased [RR = 0.92, 95% confidence interval (CI) 0.78-1.08; p = 0.28]. Of interest, a RR of 0.54 (95% CI 0.26-1.04; p < 0.068) for irreversible harm (a combination of cerebrovascular accidents, myocardial infarction and death) and a RR of 0.89 (95% CI 0.61-1.30; p = 0.56) for serious cardiovascular events (myocardial infarction, congestive heart failure, cerebrovascular accidents) both non-statistically significantly favored being randomized to placebo. CONCLUSIONS: For the development of current or future drugs for the treatment of angina, there is no obvious contraindication to the use of placebo controls and exercise tolerance testing.

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.

Drug-induced torsades de pointes and implications for drug development.

Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits.