Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study.

Potential effects of the selective ß(3)-adrenoceptor agonist mirabegron on cardiac repolarization were studied in healthy subjects. The four-arm, parallel, two-way crossover study was double-blind and placebo- and active (moxifloxacin)-controlled. After 2 baseline ECG days, subjects were randomized to one of eight treatment sequences (22 females and 22 males per sequence) of placebo crossed over with once-daily (10 days) 50, 100, or 200 mg mirabegron or a single 400-mg moxifloxacin dose on day 10. In each period, continuous ECGs were recorded at two baselines and on the last drug administration day. The lower one-sided 95% confidence interval for moxifloxacin effect on QTcI was >5 ms, demonstrating assay sensitivity. According to ICH E14 criteria, mirabegron did not cause QTcI prolongation at the 50-mg therapeutic and 100-mg supratherapeutic doses in either sex. Mirabegron prolonged QTcI interval at the 200-mg supratherapeutic dose (upper one-sided 95% CI >10 ms) in females, but not in males.

Population pharmacokinetic modeling of blood-brain barrier transport of synthetic adenosine A1 receptor agonists.

A population pharmacokinetic model is proposed for estimation of the brain distribution clearance of synthetic A1 receptor agonists in vivo. Rats with permanent venous and arterial cannulas in combination with a microdialysis probe in the striatum received intravenous infusions of 8-methylamino-N6-cyclopentyladenosine (MCPA) and 2'-deoxyribose-N6-cyclopentyladenosine (2'-dCPA) (10 mg kg(-1)). The clearance for transport from blood to the brain was estimated by simultaneous analysis of the blood and extracellular fluid concentrations using a compartmental pharmacokinetic model. The proposed pharmacokinetic model consists of three compartments describing the time course of the concentration in blood in combination with three compartments for the brain extracellular fluid concentrations. The blood clearance was 7.4 +/- 0.5 for MCPA and 7.2 +/- 1.4 ml min(-1) for 2'-dCPA. The in vivo microdialysis recoveries determined by the dynamic-no-net-flux method were independent of time with values of 0.21 +/- 0.02 and 0.22 +/- 0.01 for MCPA and 2'-dCPA, respectively. The values of the intercompartmental clearance for the distribution from blood to brain were 1.9 +/- 0.4 versus 1.6 +/- 0.3 mul min(-1) for MCPA and 2'-dCPA, respectively. It is concluded that on basis of the novel six-compartment model precise estimates of the rate of brain distribution are obtained that are independent of eventual differences in systemic exposure. The low brain distribution rates of MCPA and 2'-dCPA were consistent with in vitro tests. Furthermore, a slow elimination from the brain compartment was observed, indicating that the duration of central nervous system effects may be much longer than expected on the basis of the terminal half-life in blood.