title: A single supratherapeutic dose of rolofylline does not prolong the QTcF interval in healthy volunteers.
abstract: Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute decompensated heart failure and renal function impairment. The 30-mg dose of rolofylline administered by intravenous infusion over 4 hours for 3 days represented the anticipated recommended clinical regimen of rolofylline. This was a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study performed with a single 2-hour intravenous infusion of 60 mg rolofylline, placebo, or oral moxifloxacin in healthy subjects. Plasma samples were collected for determination of rolofylline, M1-trans, and M1-cis pharmacokinetic parameters. The upper limit of the two-sided 90% confidence interval for the placebo-adjusted least squares mean change from baseline in QTcF interval for rolofylline was less than 5 msec at every time point. Moxifloxacin demonstrated an increase in QTcF of greater than 10 msec at 2, 2.5, and 3 hours postdose, thus establishing the sensitivity of the assay to detect modest increases in QTcF interval. Mean Cmax values of 1947.4, 739.2, and 54.8 nM were attained for rolofylline and its metabolites M1-trans and M1-cis, respectively, which were 2.2- to 3.1-fold higher than historic Cmax values seen at the anticipated clinical dose and regimen. Adenosine A1 receptor antagonism from a single supratherapeutic intravenous dose of 60 mg rolofylline over 2 hours was generally well tolerated and did not prolong the QTcF interval relative to placebo.
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA. waldemar_radziszewski@merck.com
authors.forename: Waldemar
authors.initials: W
authors.lastname: Radziszewski
authors.forename: Eseng
authors.initials: E
authors.lastname: Lai
authors.forename: Nicole
authors.initials: N
authors.lastname: Lazarus Shipitofsky
authors.forename: Mark
authors.initials: M
authors.lastname: Stroh
authors.forename: Victor
authors.initials: V
authors.lastname: Dishy
authors.forename: Lingling
authors.initials: L
authors.lastname: Han
authors.forename: William
authors.initials: W
authors.lastname: Lewis
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: Ryan
authors.initials: R
authors.lastname: Lutz
authors.forename: John
authors.initials: J
authors.lastname: Wagner
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000284:Administration, Oral; D000328:Adult; D001372:Aza Compounds / Q000009:adverse effects; D018592:Cross-Over Studies; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects; D014970:Xanthines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D001372:Aza Compounds; D004232:Diuretics; D024841:Fluoroquinolones; D011804:Quinolines; D014970:Xanthines; C073525:rolofylline; D000077266:Moxifloxacin