Chemical formula: C₁₅H₁₈N₈O₅ Molecular mass: 390.354 g/mol PubChem compound: 219024
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 very low, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor produces coronary vasodilation and increases coronary blood flow (CBF).
Despite low affinity for the A2A adenosine receptor, regadenoson has high potency for increasing coronary conductance in rat and guinea pig isolated hearts, with EC50 values of 6.4 nM and 6.7-18.6 nM, respectively. Regadenoson shows selectivity (≥215-fold) for increasing coronary conductance (A2A-mediated response) relative to slowing of cardiac AV nodal conduction (A1-mediated response) as measured by AV conduction time (rat heart) or the S-H interval (guinea pig heart). Regadenoson preferentially increases blood flow in coronary relative to peripheral (forelimb, brain, pulmonary) arterial vascular beds in the anaesthetised dog.
Regadenoson causes a rapid increase in CBF which is sustained for a short duration. In patients undergoing coronary catheterisation, pulsed-wave Doppler ultrasonography was used to measure the average peak velocity (APV) of CBF before and up to 30 minutes after administration of regadenoson (400 micrograms, intravenously). Mean APV increased to greater than twice baseline by 30 seconds and decreased to less than half of the maximal effect within 10 minutes. Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because regadenoson increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, regadenoson causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. Myocardial radiopharmaceutical uptake after regadenoson administration is therefore greater in areas perfused by normal relative to stenosed arteries. The same applies to the FFR measurement where the maximal myocardial blood flow is decreased in presence of severe coronary artery stenosis.
The majority of patients experience a rapid increase in heart rate. The greatest mean change from baseline (21 bpm) occurs approximately 1 minute after administration of regadenoson. Heart rate returns to baseline within 10 minutes. Systolic blood pressure and diastolic blood pressure changes were variable, with the greatest mean change in systolic pressure of −3 mmHg and in diastolic pressure of −4 mm Hg approximately 1 minute after regadenoson administration. An increase in blood pressure has been observed in some patients (maximum systolic blood pressure of 240 mm Hg and maximum diastolic blood pressure of 138 mm Hg).
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 been shown to have little binding affinity for the A2B and A3 adenosine receptors. The incidence of a FEV1 reduction >15% from baseline after regadenoson administration was assessed in three randomised, controlled clinical studies. In the first study in 49 patients with moderate to severe COPD, the rate of FEV1 reduction >15% from baseline was 12% and 6% following regadenoson and placebo dosing, respectively (p=0.31). In the second study in 48 patients with mild to moderate asthma who had previously been shown to have bronchoconstrictive reactions to adenosine monophosphate, the rate of FEV1 reduction >15% from baseline was the same (4%) following both regadenoson and placebo dosing. In the third study in 1009 patients with mild or moderate asthma (n=537) and moderate or severe COPD (n=472) the incidence of FEV1 reduction >15% from baseline was 1.1% and 2.9% in patients with asthma (p=0.15) and 4.2% and 5.4% in patients with COPD (p=0.58) following regadenoson and placebo dosing, respectively. In the first and second studies, dyspnoea was reported as an adverse reaction following regadenoson dosing (61% for patients with COPD; 34% for patients with asthma) while no subjects experienced dyspnoea following placebo dosing. In the third study dyspnoea was reported more frequently following regadenoson (18% for patients with COPD; 11% for patients with asthma) than placebo, but at a lower rate than reported during clinical development. A relationship between increased severity of disease and the increased incidence of dyspnoea was apparent in patients with asthma, but not in patients with COPD. The use of bronchodilator therapy for symptoms was not different between regadenoson and placebo. Dyspnoea did not correlate with a decrease in FEV1.
Regadenoson is administered by intravenous injection for pharmacologic stress radionuclide MPI. The regadenoson plasma concentration-time profile in healthy volunteers is multi-exponential in nature and best characterised by 3-compartment model. The maximal plasma concentration of regadenoson is achieved within 1 to 4 minutes after injection of regadenoson 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. Within the dose range of 0.003-0.02 mg/kg (or approximately 0.18-1.2 mg) in healthy subjects, clearance, terminal half-life or volume of distribution do not appear dependent upon the dose.
Regadenoson is moderately bound to human plasma proteins (25-30%).
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. 14
Following intravenous administration of C-radiolabeled regadenoson to rats and dogs, most radioactivity (85-96%) was excreted in the form of unchanged regadenoson. These findings indicate that metabolism of regadenoson does not play a major role in the elimination of regadenoson.
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.
Up to three consecutive injections of regadenoson (100 and 200 μg) have been tested in healthy volunteers, and two consecutive doses of 400 μg in healthy volunteers, as well as in patients assessed for FFR. Transient dose dependent increases in heart rate occurred following administration of each dose of regadenoson, whereas no consistent dose-related effect on systolic blood pressure was observed. Mean plasma concentrations increased in a dose-related manner and by successive doses as observed in healthy volunteers.
A population pharmacokinetic analysis including data from subjects and patients demonstrated that regadenoson clearance decreases in parallel with a reduction in creatinine clearance (CLcr) and increases with increased body weight. Age, gender, and race have minimal effects on the pharmacokinetics of regadenoson.
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 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.
The pharmacokinetics of regadenoson in patients on dialysis has not been assessed.
Greater than 55% of the regadenoson dose is excreted unchanged in the urine and factors that decrease clearance do not affect the plasma concentration in the early stages after dosing when clinically meaningful pharmacologic effects are observed. The pharmacokinetic parameters of regadenoson have not been specifically evaluated in those with varying degrees of hepatic impairment. However, post-hoc analysis of data from the two Phase 3 clinical trials showed that the pharmacokinetics of regadenoson were not affected in a small subset of patients with laboratory values suggestive of impaired hepatic function (2.5-fold transaminase elevation or 1.5-fold elevation of serum bilirubin or prothrombin time). No dose adjustment is needed in patients with hepatic impairment.
Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of regadenoson. No dose adjustment is needed in elderly patients.
The pharmacokinetic parameters of regadenoson have not yet been studied in the paediatric population (<18 years).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, or embryo-fetal development. Signs of maternal and fetal toxicity were seen in rats and rabbits (reduced fetal weights, delays in ossification [rats], reduced litter size and number of live fetuses [rabbits]), but not teratogenicity. Fetal toxicity was noted following repeated daily administration of regadenoson, but at doses sufficiently in excess of the recommended human dose. Fertility and pre- and post-natal studies have not been conducted.
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