title: The effects of multiple doses of rolofylline on the single-dose pharmacokinetics of midazolam in healthy subjects.
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. This was a phase I, randomized, open-label, 2-period, fixed-sequence study in 19 healthy adult volunteers to examine the effect of multiple intravenous rolofylline doses on the single-dose pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. In period 1, subjects received a single oral dose of midazolam 7.5 mg on day 1. In period 2, subjects received 30 mg, 4-hour infusions of rolofylline (intended clinical dose and duration) once daily for 4 consecutive days; midazolam 7.5 mg was coadministered on day 4. The geometric mean ratios and 90% confidence intervals for AUC0-infinity and Cmax of midazolam in the presence/absence of rolofylline were 1.20 (1.12-1.29) and 1.17 (1.03-1.32), respectively. The apparent terminal half-life (t1/2) for midazolam was similar in the presence/absence of rolofylline (4.31 and 4.27 hours, respectively). The geometric mean ratios (90% confidence intervals) for AUC0-infinity and Cmax of 1'-hydroxymidazolam in the presence/absence of rolofylline were 1.04 (0.96-1.13) and 0.98 (0.84-1.14), respectively. The t1/2 for 1'-hydroxymidazolam was slightly higher in the presence relative to absence of rolofylline (4.24 and 3.17 hours, respectively). Multiple doses of intravenous rolofylline 30 mg for 4 days were generally well tolerated and did not result in clinically important inhibition of CYP3A4 as indicated by little or no change in the pharmacokinetics of midazolam.
authors.affiliation: Merck Research Laboratories, West Point, PA, USA. mark_stroh@merck.com
authors.forename: Mark
authors.initials: M
authors.lastname: Stroh
authors.forename: Victor
authors.initials: V
authors.lastname: Dishy
authors.forename: Waldemar
authors.initials: W
authors.lastname: Radziszewski
authors.forename: Eunhee
authors.initials: E
authors.lastname: Hwang
authors.forename: Nicole
authors.initials: N
authors.lastname: Lazarus-Shipitofsky
authors.forename: Howard
authors.initials: H
authors.lastname: Dittrich
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: Ryan
authors.initials: R
authors.lastname: Lutz
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Eseng
authors.initials: E
authors.lastname: Lai
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D008875:Middle Aged; D014970:Xanthines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D004232:Diuretics; D014970:Xanthines; C073525:rolofylline; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam