title: Development of a precipitation-resistant solution formulation to increase in vivo exposure of a poorly water-soluble compound.
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.
authors.affiliation: Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, USA. lori.burton@bms.com
authors.forename: Lori
authors.initials: L
authors.lastname: Burton
authors.forename: William
authors.initials: W
authors.lastname: Ying
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gandhi
authors.forename: Ronald
authors.initials: R
authors.lastname: West
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.forename: Simon
authors.initials: S
authors.lastname: Zhou
authors.forename: Keyur
authors.initials: K
authors.lastname: Shah
authors.forename: Jinling
authors.initials: J
authors.lastname: Chen
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Shen
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011232:Chemical Precipitation; D018592:Cross-Over Studies; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019999:Pharmaceutical Solutions; D026902:Potassium Channel Blockers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013045:Species Specificity
chemical_list: C576230:(7-(3,4-dichlorophenyl)-5-methyl-4,7-dihydropyrazolo(1,5-a)pyrimidin-6-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone; D000889:Anti-Arrhythmia Agents; D019999:Pharmaceutical Solutions; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D011743:Pyrimidines