A Population Pharmacokinetic/Pharmacodynamic Analysis of Regadenoson, an Adenosine A2A-Receptor Agonist, in Healthy Male Volunteers

Gordi, Toufigh; Frohna, Paul; Sun, Hai Ling; Wolff, Andrew; Belardinelli, Luiz; Lieu, Hsiao

doi:10.2165/00003088-200645120-00005

Cited by 72 publications

(82 citation statements)

References 11 publications

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“…7 This presumably causes the brief ''mini-panic attack'' feeling that patients often experience beginning 30-90 seconds after administration of regadenoson or adenosine. As observed in other studies, 3,8 heart rate increases with escalating doses of regadenoson, although the incremental increase is not directly proportional to dose. Figure 3 and Appendix 2 of Townsend et al 2 demonstrate an additional 5 bpm heart rate increase with a second dose of 0.4 mg of regadenoson over and above the 45 bpm heart rate increase observed with the first dose.…”

supporting

confidence: 81%

“…A reasonable re-dosing interval can be considered by an analysis of regadenoson pharmacokinetics and pharmacodynamics. In 2 contributions, Gordi et al 8,9 found regadenoson's pharmacokinetics best described by a 3-compartment model with linear clearance (whereby drug removal is proportional to time) and tri-phasic half-lives. The initial half-life of 2-4 minutes corresponds roughly to the drug's appearance in the vascular space and other tissues following IV injection and has a volume of distribution of 11.5 L. The intermediate half-life of &30 minutes corresponds roughly to distribution into other tissues with a volume of distribution of 59 L. The combined duration of these 2 halflives over 4-5 half-lives appears to correspond to its loss of pharmacodynamic effects.…”

mentioning

confidence: 99%

“…The terminal elimination half-life is &120 minutes and reflects redistribution from tissue compartments into the vascular compartment, as well as loss of drug from the body via the renal system. 8,10,11 The major elimination pathway is renal with 58% of the dose cleared by the kidneys both by glomerular filtration and tubular secretion. 8 In patients with creatinine clearance \80 mLÁmin -1 , regadenoson's clearance decreases with a corresponding increase in plasma concentration and prolongation of the terminal half-life.…”

mentioning

confidence: 99%

“…8,10,11 The major elimination pathway is renal with 58% of the dose cleared by the kidneys both by glomerular filtration and tubular secretion. 8 In patients with creatinine clearance \80 mLÁmin -1 , regadenoson's clearance decreases with a corresponding increase in plasma concentration and prolongation of the terminal half-life. 9 Throughout the 3 distinct half-lives, regadenoson is distributed from the vascular compartment into various tissues and redistributed back, resulting in mean plasma concentrations of [2 and [1 ngÁmL -1 at 1 and 2 hours following 0.4 mg of regadenoson, respectively (estimates obtained from Figure 3 of Gordi et al).…”

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confidence: 99%

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When to re-dose regadenoson?

Thomas

Jolly

Safani

2017

Journal of Nuclear Cardiology

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Since FDA approval in 2008, regadenoson, an A2A adenosine receptor agonist, has become the most commonly used pharmacological stress testing agent in the U.S. 1 In this issue of the Journal, Townsend et al 2 address the important question of how to manage redosing of regadenoson if it were to become necessary. This information would be helpful, for example, if the FDA approved 0.4 mg (400 lg) dose of regadenoson were administered intravenously (IV) but the radiotracer became inadvertently unavailable or in the case of an infiltrated IV line resulting in the subcutaneous administration of regadenoson.Townsend et al 2 evaluated the pharmacokinetics (the study of the time course of the drug's absorption, distribution, metabolism, and excretion) and pharmacodynamics (the study of the biochemical and physiological effects of a drug on the body) of different doses of regadenoson administered every 10 minutes (min). To do so, they randomized 36 healthy men and women, mean age 38 years, who were not on any medications, to receive either 3 separate doses of 0.1 mg 10 minutes apart, 3 doses of 0.2 mg 10 minutes apart, 2 doses of 0.4 mg 10 minutes apart or 2 or 3 doses of placebo 10 minutes apart. In addition to measuring plasma concentrations of regadenoson, they studied the pharmacodynamic effect on blood pressure and heart rate as primary endpoints.Work by Lieu et al 3 evaluated the pharmacodynamic effect of escalating doses of regadenoson on coronary velocity using a coronary Doppler flow wire. They found that regadenoson doses of 0.1 mg, 0.3 and 0.4 mg increased peak velocity above baseline by 3.0 ± 0.6 (SD), 3.4 ± 0.8, and 3.1 ± 0.5 times, respectively. As flow increases linearly with velocity, by the formula [Flow = p r 2 (average velocity)(0.5) 9 60] with r equal to vessel radius, peak myocardial blood flow would thus increase to a similar degree with either 0.1 or 0.4 mg of regadenoson. However, the 0.4 mg dose was selected for use with MPI as it produced a sustained velocity 2.5 times above baseline for 2.3 minutes compared to \2 minutes for smaller doses. 3,4 Townsend et al 2 found 0.4 mg of regadenoson to result in mean plasma concentrations of &18 and &9 ngÁmL -1 at 3 and 9 min, respectively. Given earlier findings of Lieu et al 3 that coronary velocity remains C2 times baseline for a mean of 9 minutes, a concentration of 9 ngÁmL -1 would correlate with a &twofold increase in velocity.Using the 0.1 mg dose, which Lieu et al 3 found to increase coronary velocity threefold, Townsend et al 2 found 0.1 mg to result in a mean concentration of &5 ngÁmL -1 measured 3 minutes post dosing. This was the first time of measurement in their study. Correlating this dose with coronary velocity in the study of Lieu et al 3 is difficult, as coronary velocity had decreased to \2 times baseline by 3 minutes with this dose. Nonetheless, the coronary velocity curves Lieu et al 3 observed are consistent with a significant impact on coronary velocity remaining at 3 minutes in relation to a plasma concentration of &5 ngÁmL -1 .Thus, ...

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confidence: 99%

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When to re-dose regadenoson?

Thomas

Jolly

Safani

2017

Journal of Nuclear Cardiology

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“…Consistent with this, the prevalence of adverse events during administration of regadenoson in healthy volunteers was greater in standing than in supine subjects. 27 Therefore, in the presence of autonomic dysfunction that attenuates a reflex increase of heart rate to maintain blood pressure and/or diminished sympathoexcitation, the A2A-mediated effect of regadenoson to reduce peripheral resistance may lead to a greater normal drop in blood pressure and cardiac output. In dogs and rats treated with hexamethonium, a blocker of impulse transmission through autonomic nerve ganglia, regadenoson administration (5 lg/kg) did not increase heart rate, and the drop in blood pressure was much greater than in untreated control animals.…”

Section: Asystolementioning

confidence: 99%