Relationship between concentrations of adinazolam and its primary metabolite in plasma and therapeutic/untoward effects in the treatment of panic disorder.
Adinazolam mesylate, a triazolobenzodiazepine with antidepressant and anxiolytic activity, has been shown in several studies to treat panic disorder effectively. This report presents the results of analysis of concentrations in plasma of adinazolam and its primary metabolite, N-desmethyladinazolam (NDMAD), determined as a part of a flexible-dose, double-blind study of the efficacy of adinazolam mesylate sustained release tablets in the treatment of panic disorder with agoraphobia. Dosages administered in the study were titrated from 30 mg/day up to a maximum of 120 mg/day. Concentrations in plasma were determined by high-performance liquid chromatography at clinical evaluations at the end of treatment weeks 1, 2, and 4. The concentrations of both compounds were proportional to the administered dose. An inverted U-shaped concentration-response curve was apparent, where response was based on a priori definitions contained in the study protocol. However, this was probably a result of the flexible-dose study design used. By use of the post hoc definitions of response, as measured by the Clinician's Global Improvement Scale and the total panic attack frequency, logistic regression analysis resulted in more adequate predictions of actual response frequencies. Results indicate that NDMAD contributes to the therapeutic effects of adinazolam mesylate sustained release tablets in the treatment of panic disorder. The exact contributions of adinazolam and NDMAD to response in panic disorder could not be determined, because of the correlation between adinazolam and NDMAD concentrations on multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)
Fleishaker
J C
JC
Clinical Pharmacokinetics Unit, Upjohn Company, Kalamazoo, Michigan 49007.
Greist
J H
JH
Jefferson
J W
JW
Sheridan
A Q
AQ
D000379:Agoraphobia / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D016584:Panic Disorder / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D010555:Personality Inventory
D000928:Antidepressive Agents; D003692:Delayed-Action Preparations; D001569:Benzodiazepines; C074080:adinazolam mesylate; C050132:mono-N-demethyladinazolam