CLINICAL PHARMACOLOGY
Mechanism of Action
Regadenoson is a low affinity agonist (Ki ≈ 1.3 µM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 µM), and weak, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF).
Pharmacodynamics
Coronary Blood Flow
Lexiscan causes a rapid increase in CBF which is sustained for a short duration. In patients undergoing coronary catheterization, pulsed-wave Doppler ultrasonography was used to measure the average peak velocity (APV) of coronary blood flow before and up to 30 minutes after administration of regadenoson (0.4 mg, intravenously). Mean APV increased to greater than twice baseline by 30 seconds and decreased to less than twice the baseline level within 10 minutes [see Clinical Pharmacology (12.3)].
Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because Lexiscan increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Lexiscan causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after Lexiscan administration is therefore greater in areas perfused by normal relative to stenosed arteries.
Effect of Aminophylline
Aminophylline (100 mg, administered by slow iv injection over 60 seconds) injected 1 minute after 0.4 mg Lexiscan in subjects undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to Lexiscan as measured by pulsed-wave Doppler ultrasonography [see Overdosage (10)].
Effect of Caffeine
Ingestion of caffeine decreases the ability to detect reversible ischemic defects. In a placebo-controlled, parallel group clinical study, patients with known or suspected myocardial ischemia received a baseline rest/stress MPI followed by a second stress MPI. Patients received caffeine or placebo 90 minutes before the second Lexiscan stress MPI. Following caffeine administration (200 or 400 mg), the mean number of reversible defects identified was reduced by approximately 60%. This decrease was statistically significant [see Drug Interactions (7.1) and Patient Counseling Information (17)].
Hemodynamic Effects
In clinical studies, the majority of patients had an increase in heart rate and a decrease in blood pressure within 45 minutes after administration of Lexiscan. Maximum hemodynamic changes after Lexiscan and Adenoscan in Studies 1 and 2 are summarized in Table 4.
Table 4 Hemodynamic Effects in Studies 1 and 2
Vital Sign Parameter
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Lexiscan
N = 1,337
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Adenoscan
N = 678
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Heart Rate
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> 100 bpm
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22%
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13%
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Increase > 40 bpm
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5%
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3%
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Systolic Blood Pressure
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< 90 mm Hg
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2%
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3%
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Decrease > 35 mm Hg
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7%
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8%
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≥ 200 mm Hg
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1.9%
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1.9%
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Increase ≥ 50 mm Hg
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0.7%
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0.8%
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≥ 180 mm Hg and increase of ≥ 20 mm Hg from baseline
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4.6%
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3.2%
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Diastolic Blood Pressure
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< 50 mm Hg
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2%
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4%
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Decrease > 25 mm Hg
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4%
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5%
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≥ 115 mm Hg
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0.9%
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0.9%
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Increase ≥ 30 mm Hg
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0.5%
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1.1%
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Respiratory Effects
The A2B and A3 adenosine receptors have been implicated in the pathophysiology of bronchoconstriction in susceptible individuals (i.e., asthmatics). In in vitro studies, regadenoson has not been shown to have appreciable binding affinity for the A2B and A3 adenosine receptors.
In a randomized, placebo-controlled clinical trial (Study 3) of 999 subjects with a diagnosis, or risk factors for, coronary artery disease and concurrent asthma or COPD, the incidence of respiratory adverse reactions (dyspnea, wheezing) was greater with Lexiscan compared to placebo. Moderate (2.5%) or severe (<1%) respiratory reactions were observed more frequently in the Lexiscan group compared to placebo [see Adverse Reactions (6.1)].
Pharmacokinetics
In healthy volunteers, the regadenoson plasma concentration-time profile is multi-exponential in nature and best characterized by 3-compartment model. The maximal plasma concentration of regadenoson is achieved within 1 to 4 minutes after injection of Lexiscan and parallels the onset of the pharmacodynamic response. The half-life of this initial phase is approximately 2 to 4 minutes. An intermediate phase follows, with a half-life on average of 30 minutes coinciding with loss of the pharmacodynamic effect. The terminal phase consists of a decline in plasma concentration with a half-life of approximately 2 hours [see Clinical Pharmacology (12.2)]. Within the dose range of 0.3–20 µg/kg in healthy subjects, clearance, terminal half-life or volume of distribution do not appear dependent upon the dose.
A population pharmacokinetic analysis including data from subjects and patients demonstrated that regadenoson clearance decreases in parallel with a reduction in creatinine clearance and clearance increases with increased body weight. Age, gender, and race have minimal effects on the pharmacokinetics of regadenoson.
Special Populations
Renally Impaired Patients: The disposition of regadenoson was studied in 18 subjects with various degrees of renal function and in 6 healthy subjects. With increasing renal impairment, from mild (CLcr 50 to < 80 mL/min) to moderate (CLcr 30 to < 50 mL/min) to severe renal impairment (CLcr < 30 mL/min), the fraction of regadenoson excreted unchanged in urine and the renal clearance decreased, resulting in increased elimination half-lives and AUC values compared to healthy subjects (CLcr ≥ 80 mL/min). However, the maximum observed plasma concentrations as well as volumes of distribution estimates were similar across the groups. The plasma concentration-time profiles were not significantly altered in the early stages after dosing when most pharmacologic effects are observed. No dose adjustment is needed in patients with renal impairment.
Patients with End Stage Renal Disease: The pharmacokinetics of regadenoson in patients on dialysis has not been assessed.
Hepatically Impaired Patients: The influence of hepatic impairment on the pharmacokinetics of regadenoson has not been evaluated. Because greater than 55% of the dose is excreted in the urine as unchanged drug and factors that decrease clearance do not affect the plasma concentration in the early stages after dosing when clinically meaningful pharmacologic effects are observed, no dose adjustment is needed in patients with hepatic impairment.
Geriatric Patients: Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of regadenoson. No dose adjustment is needed in elderly patients.
Metabolism
The metabolism of regadenoson is unknown in humans. Incubation with rat, dog, and human liver microsomes as well as human hepatocytes produced no detectable metabolites of regadenoson.
Excretion
In healthy volunteers, 57% of the regadenoson dose is excreted unchanged in the urine (range 19–77%), with an average plasma renal clearance around 450 mL/min, i.e., in excess of the glomerular filtration rate. This indicates that renal tubular secretion plays a role in regadenoson elimination.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Regadenoson was negative in the Ames bacterial mutation assay, chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and mouse bone marrow micronucleus assay.
Long-term animal studies have not been conducted to evaluate Lexiscan's carcinogenic potential or potential effects on fertility.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Reproduction studies were conducted in rabbits and rats using doses of Lexiscan that were 2 to 20 times (rats) and 4 to 20 times (rabbits) the maximum recommended human dose (MRHD), based on body surface area comparison.
When administered to rabbits during organogenesis, regadenoson caused maternal toxicity including tachypnea, soft, liquid or scant feces, and localized alopecia in all treated groups, and caused reduction in body weight and feed consumption at 0.3 and 0.5 mg/kg/day (12 and 20 X MRHD, respectively). At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity occurred along with decreased number of live fetuses, reduced fetal body weight, and occurrence of fetal variations and malformations. At regadenoson doses equivalent to 20 times the MRHD, resorptions were increased and fetal body weights reduced. Fetal malformations included microphthalmia (1/116 at 20 X MRHD), interrelated vertebrae/rib alterations (2/145 and 2/116 each at 12 and 20 X MRHD), and misaligned caudal vertebrae (3/145 at 12 X MRHD). Fetal toxicity was only observed at maternally toxic doses. The no effect dose level for fetal toxicity is 0.1 mg/kg (4 X MRHD). A no effect dose level was not identified for maternal toxicity.
When regadenoson was administered to pregnant rats during the period of major organogenesis, 4/25 rats from the 1.0 mg/kg/day group (20 X MRHD) and 1/25 rats from the 0.8 mg/kg (16 X MRHD) group died immediately following the first dose of regadenoson. All dams had decreased motor activity and one was gasping post-dosing. At doses ≥ 0.5 mg/kg (10 X MRHD), maternal toxicity included decreased motor activity, increased limb extension, excess salivation, and reduction in body weight and feed consumption. At doses ≥ 0.5 mg/kg, fetal body weights were significantly reduced and significant ossification delays were observed in fore- and hind limb phalanges and metatarsals. Skeletal malformations included delayed ossification of the skull (1/167), and hemivertebra present at a thoracic vertebra (1/167), observed at 16-20 X MRHD, and small arches of a lumbar and sacral vertebrae (1/174) observed at 2 X MRHD. The no effect dose level for maternal toxicity is 0.1 mg/kg/day (2 X MRHD).
Cardiomyopathy
Minimal cardiomyopathy (myocyte necrosis and inflammation) was observed in rats following single dose administration of regadenoson. Increased incidence of minimal cardiomyopathy was observed on day 2 in males at doses of 0.08, 0.2 and 0.8 mg/kg (1/5, 2/5, and 5/5) and in females (2/5) at 0.8 mg/kg. In a separate study in male rats, the mean arterial pressure was decreased by 30 to 50% of baseline values for up to 90 minutes at regadenoson doses of 0.2 and 0.8 mg/kg, respectively. No cardiomyopathy was noted in rats sacrificed 15 days following single administration of regadenoson. The mechanism of the cardiomyopathy induced by regadenoson was not elucidated in this study but was associated with the hypotensive effects of regadenoson. Profound hypotension induced by vasoactive drugs is known to cause cardiomyopathy in rats.
Local Irritation
Intravenous administration of Lexiscan to rabbits resulted in perivascular hemorrhage, vein vasculitis, inflammation, thrombosis and necrosis, with inflammation and thrombosis persisting through day 8 (last observation day). Perivascular administration of Lexiscan to rabbits resulted in hemorrhage, inflammation, pustule formation and epidermal hyperplasia, which persisted through day 8 except for the hemorrhage which resolved. Subcutaneous administration of Lexiscan to rabbits resulted in hemorrhage, acute inflammation, and necrosis; on day 8 muscle fiber regeneration was observed.
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