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PII‐33
Author(s) -
Raje S. V.,
Parks V.,
Plotka A.,
Patat A. A.,
Dupain T.
Publication year - 2006
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.2005.12.158
Subject(s) - bioequivalence , cmax , bioavailability , pharmacology , pharmacokinetics , dosing , chemistry , crossover study , antagonist , clinical pharmacology , medicine , receptor , biochemistry , alternative medicine , pathology , placebo
BACKGROUND/AIMS Lecozotan is a new potent and silent 5‐HT 1A antagonist being developed for the treatment of cognitive deficits associated with Alzheimer's disease. Pharmacokinetics (PK) and brain receptor occupancy data currently justify a twice‐daily dosing regimen with the immediate release (IR) formulation and there is a need to develop a modified release formulation to allow once‐daily dosing of Lecozotan. The objective of this study was to assess the relative bioavailability of 3 new sustained/modified release (SR) formulations compared to the IR formulation. METHODS This was a single‐dose, randomized, 4‐period, crossover study in 20 subjects who received 5 mg of all 4 (1 IR and 3 SR) formulations. Lecozotan PK parameters were compared between the 4 formulations using statistical analyses. RESULTS Based on AUC 0‐∞ , the SR‐fast and SR‐medium formulations were bioequivalent to the IR formulation. C max with the SR‐fast and SR‐medium formulations was ∼ 1/3 rd that of the IR formulation. C max /C 24h ratios for the SR‐fast and SR‐medium formulations were 2.8 and 2.3, respectively, in comparison to 23 for the IR formulation. Treatment‐emergent adverse events were substantially less frequent with the SR formulations (1 vs. 14 for IR), presumably because of reduced C max . CONCLUSIONS Bioequivalence with the IR formulation suggests that the SR‐fast and SR‐medium formulations are suitable for further development and the low C max /C 24h ratios show favorable properties for once daily administration. Clinical Pharmacology & Therapeutics (2005) 79 , P45–P45; doi: 10.1016/j.clpt.2005.12.158