PMID- 20213833
OWN - NLM
STAT- MEDLINE
DCOM- 20101028
LR  - 20181113
IS  - 1520-6017 (Electronic)
IS  - 0022-3549 (Print)
IS  - 0022-3549 (Linking)
VI  - 99
IP  - 8
DP  - 2010 Aug
TI  - Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an 
      ordered categorical measure.
PG  - 3628-41
LID - 10.1002/jps.22093 [doi]
AB  - 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.
CI  - (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association
FAU - Kamal, Mohamed A
AU  - Kamal MA
AD  - F. Hoffmann-La Roche Inc, Modeling & Simulation, Nutley, NJ 07110, USA. 
      mohamed.kamal@roche.com
FAU - Smith, David E
AU  - Smith DE
FAU - Cook, Jack
AU  - Cook J
FAU - Feltner, Douglas
AU  - Feltner D
FAU - Moton, Allen
AU  - Moton A
FAU - Ouellet, Daniele
AU  - Ouellet D
LA  - eng
GR  - R01 GM035498/GM/NIGMS NIH HHS/United States
GR  - T32 GM007767/GM/NIGMS NIH HHS/United States
GR  - T32 GM007767-32/GM/NIGMS NIH HHS/United States
GR  - GM007767/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Pharm Sci
JT  - Journal of pharmaceutical sciences
JID - 2985195R
RN  - 0 (Hypnotics and Sedatives)
RN  - O26FZP769L (Lorazepam)
SB  - IM
MH  - Adult
MH  - Algorithms
MH  - Area Under Curve
MH  - Computer Simulation
MH  - Cross-Over Studies
MH  - Dizziness/*chemically induced
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Hypnotics and Sedatives/*pharmacology
MH  - Logistic Models
MH  - Lorazepam/*pharmacology
MH  - Male
MH  - Pharmacokinetics
MH  - Population
MH  - Sleep Stages/*drug effects
MH  - Tandem Mass Spectrometry
PMC - PMC2919060
MID - NIHMS220452
EDAT- 2010/03/10 06:00
MHDA- 2010/10/29 06:00
PMCR- 2010/08/10
CRDT- 2010/03/10 06:00
PHST- 2010/03/10 06:00 [entrez]
PHST- 2010/03/10 06:00 [pubmed]
PHST- 2010/10/29 06:00 [medline]
PHST- 2010/08/10 00:00 [pmc-release]
AID - S0022-3549(15)32515-6 [pii]
AID - 10.1002/jps.22093 [doi]
PST - ppublish
SO  - J Pharm Sci. 2010 Aug;99(8):3628-41. doi: 10.1002/jps.22093.