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Safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ascending single doses of SRA‐333 in healthy subjects
Author(s) -
Patat A. A.,
Parks V.,
Raje S.,
Plotka A.,
Chassard D.
Publication year - 2004
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.2003.11.080
Subject(s) - tolerability , pharmacokinetics , medicine , placebo , pharmacodynamics , adverse effect , pharmacology , clinical pharmacology , dosing , safety pharmacology , anesthesia , drug , alternative medicine , pathology
SRA‐333 is a new potent and silent 5HT 1a antagonist which increased glutamatergic and cholinergic neurotransmission during cognitive processes. SRA‐333 is proposed for the treatment of cognitive deficits associated with Alzheimer's disease. This was a randomized, double‐blind, placebo‐controlled, sequential, ascending single dose study in 24 healthy subjects to assess the safety, tolerability, PK and PD of SRA‐333. Three dose levels (2, 5 and 10 mg) were assessed in cohorts of 8 subjects (6 active and 2 placebo). Assessments consisted of safety evaluation (vital signs, ECG, lab tests), up to 48 hours after dosing, determination of SRA‐333 PK profile and cognitive assessment using the Cognitive Drug Research battery (Reading, UK) exploring attention, sensori‐motor tasks and working and episodic memory. SRA‐333 was well‐tolerated up to a dose of 10 mg where dose limiting mild to moderate CNS adverse events occurred (light headedness, sensorial disturbances, dizziness). No individual clinically significant sustained individual drug‐related changes were recorded in vital signs, ECGs and routine laboratory tests. No clinically relevant impairment in cognitive functions were observed. SRA‐333 was rapidly absorbed (t max ≃ 0.5h) and eliminated (half‐life ≃ 6 to 8 hours). Plasma concentrations increased in a linear‐proportional manner with increasing doses. In summary, SRA‐333 was safe and well‐tolerated up to a dose of 10 mg. Its pharmacokinetic profile allowed a twice daily dosage regimen. Clinical Pharmacology & Therapeutics (2004) 75 , P21–P21; doi: 10.1016/j.clpt.2003.11.080