Abstract:
:In vitro and in vivo investigations were conducted to develop a suitable formulation for early toxicology and clinical studies of ((R)-7-(3,4-dichlorophenyl)-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (Compound A), a nonionizable and poorly water-soluble compound that selectively inhibits the ultrarapid potassium current (IKur) and is intended for the treatment of arrhythmia. Various nonaqueous solution formulations were evaluated, in vitro, for ability to prevent or delay precipitation of Compound A from solution following dilution with water. The plasma exposures of precipitation-resistant solutions, non precipitation-resistant solutions, and aqueous suspensions were then compared in rats, dogs, and/or humans. The data indicated that a solubilized, precipitation-resistant formulation achieved the highest plasma concentrations in all species and also improved dose proportionality, particularly in rats. Development of such formulations may be highly valuable for achieving in vivo blood levels often required for successful toxicological and early clinical evaluation of poorly soluble compounds.
journal_name
Int J Pharmjournal_title
International journal of pharmaceuticsauthors
Burton L,Ying W,Gandhi R,West R,Huang C,Zhou S,Shah K,Chen J,Shen Xdoi
10.1016/j.ijpharm.2012.04.075subject
Has Abstractpub_date
2012-08-20 00:00:00pages
94-101issue
1-2eissn
0378-5173issn
1873-3476pii
S0378-5173(12)00421-8journal_volume
433pub_type
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