title: Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measure.
abstract: Categorical measures of lorazepam sleepiness and dizziness were modeled to identify differences in pharmacodynamic (PD) parameters between these adverse events (AEs). Differences in data-derived PD parameters were compared with relative incidence rates in the drug label (15.7% and 6.9%, respectively). Healthy volunteers (n = 20) received single oral doses of 2 mg lorazepam or placebo in a randomized, double-blind, cross-over fashion. A seven-point categorical scale measuring the intensity of AEs was serially administered over 24 h. The maximum score (MaxS), and area under the effect curve (AUEC) were determined by noncompartmental methods and compared using a paired t-test. Individual scores were modeled using a logistic function implemented in NONMEM. AUEC and MaxS for sleepiness were significantly higher than dizziness (20.35 vs. 9.76, p < 0.01) and (2.35 vs. 1.45, p < 0.01). Model slope estimates were similar for sleepiness and dizziness (0.21 logits x mL/ng vs. 0.19 logits x mL/ng), but baseline logits were significantly higher for sleepiness (-2.81 vs. -4.34 logits). Data-derived PD parameters were in concordance with label incidence rates. The higher intensity of sleepiness may be directly related to baseline (no drug present) while the increase in intensity as a result of drug was relatively similar for both AEs.
authors.affiliation: F. Hoffmann-La Roche Inc, Modeling & Simulation, Nutley, NJ 07110, USA. mohamed.kamal@roche.com
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kamal
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
authors.forename: Jack
authors.initials: J
authors.lastname: Cook
authors.forename: Douglas
authors.initials: D
authors.lastname: Feltner
authors.forename: Allen
authors.initials: A
authors.lastname: Moton
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
mesh_terms: D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D003198:Computer Simulation; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D016015:Logistic Models; D008140:Lorazepam / Q000494:pharmacology*; D008297:Male; D010599:Pharmacokinetics; D011153:Population; D012894:Sleep Stages / Q000187:drug effects*; D053719:Tandem Mass Spectrometry
chemical_list: D006993:Hypnotics and Sedatives; D008140:Lorazepam