Pharmacokinetics of MDL 26479, a novel benzodiazepine inverse agonist, in normal volunteers.
MDL 26479 is a new drug undergoing clinical evaluation for the treatment of depression and for memory loss associated with Alzheimer's disease. As part of a dose tolerance trial, the single- (SD) and multiple-dose (MD) pharmacokinetics of MDL 26479 were evaluated in healthy male volunteers. SDs ranging from 2 to 465 mg, and doses of 30, 60, and 120 mg administered twice daily for 28 d, were examined. Serial blood samples were collected for up to 48 h. Plasma MDL 26479 concentrations were determined by HPLC. Plasma MDL 26479 concentration versus time profiles increased rapidly, followed by multiexponential decline. Time to maximum plasma concentration increased over the 230-fold SD range from 0.5 to 3.8 h. Maximum concentrations and areas under the concentration versus time curves increased disproportionately with dose. Apparent oral clearance estimates decreased from 52.9 to 13.8 Lh-1. MD pharmacokinetic parameters for doses from 30 to 120 mg were consistent with those observed following SD, thus indicating that SD pharmacokinetics are predictive of MD. SD and MD terminal half-life estimates were similar and independent of dose.
Robbins
D K
DK
Department of Pharmacokinetics and Bioanalytics, Hoèchst Marion Roussel, Kansas City, MO 64134-0627, USA. USMARLDN@IBMMAIL.COM
Hutcheson
S J
SJ
Miller
T D
TD
Green
V I
VI
Bhargava
V O
VO
Weir
S J
SJ
D000284:Administration, Oral; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000928:Antidepressive Agents; D058785:GABA-A Receptor Agonists; D014230:Triazoles; C065324:suritozole