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Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measure.

Author(s): Kamal MA, Smith DE, Cook J, Feltner D, Moton A, Ouellet D

Affiliation(s): F. Hoffmann-La Roche Inc, Modeling & Simulation, Nutley, NJ 07110, USA. mohamed.kamal@roche.com

Publication date & source: 2010-08, J Pharm Sci., 99(8):3628-41.

Publication type: Randomized Controlled Trial; Research Support, N.I.H., Extramural

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. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

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