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Feasibility of assessing differential pharmacodynamic (PD)/adverse events (AE) profiles on CNS agents
Author(s) -
Moton A.,
Ouellet D.,
Morlock R.,
Nyberg J.,
Feltner D.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.105
Subject(s) - somnolence , pharmacodynamics , medicine , nausea , tolerability , placebo , visual analogue scale , adverse effect , lorazepam , crossover study , pharmacology , anesthesia , pharmacokinetics , alternative medicine , pathology
Background The AE profile of psychotropics is an important opportunity for differentiation of new drugs in development relative to marketed competitors. This study was designed to assess the feasibility of using different subjective scales as biomarkers of PD response using 4 model CNS drugs. Methods 20 healthy subjects were randomized in a double‐blind, single dose, 5 way crossover study in a Phase 1 clinic. Treatments were atomoxetine (A, 80 mg), olanzapine (O, 10 mg), lorazepam (L, 2 mg), paroxetine (P, 40 mg) and placebo (PCB). PD responses were measured up to 24 hrs post‐dose using Visual Analogue Scale (VAS, 6 items), and Likert scales (7‐point ordered categorical, 70 items) to assess items like somnolence, dizziness, nausea, restlessness, etc. ANCOVA analyses were conducted on peak change and time‐average area under the curve vs. PCB. Results Different PD profiles (Likert and VAS) and time course of PD response were noted for the 4 model drugs. For L and O, CNS depressant activities such as sleepy, confused, poor balance, dizzy, and difficulty concentrating, were different from PCB. Decreases in DSST were also significant (L, O). A different pattern of PD effects (e.g., dry mouth, sweating, hot or flushed, excited, nervous, gastrointestinal (GI) effects were observed with A. Only GI effects were significant with P. Conclusions Different PD/AE profiles can be detected in a small Phase 1 study; and may be used as biomarkers to compare potency and tolerability of new drugs relative to marketed compounds. Clinical Pharmacology & Therapeutics (2005) 77 , P27–P27; doi: 10.1016/j.clpt.2004.11.105