A population pharmacokinetic/pharmacodynamic analysis of regadenoson, an adenosine A2A-receptor agonist, in healthy male volunteers.
OBJECTIVE
The aims of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of regadenoson (CVT-3146) in healthy, male volunteers.


METHODS
Thirty-six healthy, male volunteers aged 18-50 years were included in this randomised, double-blind, crossover, placebo-controlled study to evaluate single intravenous bolus doses of regadenoson that ranged from 0.1 to 30.0 micro g/kg. Subjects received one dose of regadenoson or placebo on successive days while supine, then the same dose of regadenoson or placebo on successive days while standing. As part of the safety evaluation, vital signs and adverse events were monitored and recorded throughout the course of the study in all subjects. Up to 20 plasma samples were collected for regadenoson concentration determination within the 24 hours after each supine dosage. All urine was collected during the 24-hour time period post-dose and an aliquot was used for the determination of the regadenoson concentration. Heart rate and blood pressure were recorded at many of the same timepoints that the samples for the pharmacokinetic analysis were taken. A non linear mixed-effect modelling approach, using the software NONMEM, was utilised in modelling the plasma and urine concentration-time profiles and temporal changes in heart rate after regadenoson administration in the supine position. The influences of several covariates, including bodyweight, body mass index and age, on pharmacokinetic model parameters were investigated.


RESULTS
Adverse events were more prevalent at regadenoson doses above 3 micro g/kg, and the increase in the occurrence of adverse events was dose-related. Most of the adverse events were related to vasodilation and an increase in heart rate and were generally of mild to moderate severity. Based on the severity and frequency of adverse events, the maximum tolerated doses of regadenoson were deemed to be 10 micro g/kg in the standing position and 20 micro g/kg in the supine position. The pharmacokinetics of regadenoson were successfully described by a three-compartment model with linear clearance. Following intravenous bolus dose administration, regadenoson was rapidly distributed throughout the body, followed by relatively slower elimination (terminal elimination half-life of approximately 2 hours). The clearance was estimated to be 37.8 L/h, with renal excretion accounting for approximately 58% of the total elimination. The volume of distribution of the central compartment and the volume of distribution at steady state were estimated to be 11.5L and 78.7L, respectively. Individual pharmacokinetic parameter estimates were fixed in the pharmacodynamic model, where changes in heart rate were related to plasma drug concentrations using a Michaelis-Menten model. The maximum heart rate increase (Emax) and plasma regadenoson concentration causing a 50% increase in the maximum heart rate (EC50) were estimated to be 76 beats per minute and 12.3 ng/mL, respectively. None of the tested covariates was found to be correlated with any of the pharmacokinetic model parameters.


CONCLUSIONS
The pharmacokinetics and the effects of regadenoson on heart rate were successfully described using pharmacokinetic/pharmacodynamic modelling. The lack of a correlation between the model estimates and various baseline patient demographics supports unit-based dose administration of regadenoson.
Gordi
Toufigh
T
CV Therapeutics Inc, Palo Alto, CA 94304, USA.
Frohna
Paul
P
Sun
Hai-Ling
HL
Wolff
Andrew
A
Belardinelli
Luiz
L
Lieu
Hsiao
H
D058908:Adenosine A2 Receptor Agonists; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006261:Headache / Q000139:chemically induced; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009325:Nausea / Q000139:chemically induced; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D014839:Vomiting / Q000139:chemically induced
D058908:Adenosine A2 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; D014665:Vasodilator Agents; C430916:regadenoson