title: Improved pharmacokinetics of AMG 517 through co-crystallization. Part 1: comparison of two acids with corresponding amide co-crystals.
abstract: The dissolution and pharmacokinetics (PK) of two carboxylic acid co-crystals (cinnamic acid and benzoic acid) with the corresponding amide co-crystals (cinnamamide and benzamide) of AMG 517 were investigated. Powder and intrinsic dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. The four co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF than the free base. This correlated with a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations. When contrasting the acid to its corresponding amide co-crystal, cinnamamide shows improvement over cinnamic acid, while benzamide and benzoic acid perform similarly.
authors.affiliation: Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. mstanton@amgen.com
authors.forename: Mary K
authors.initials: MK
authors.lastname: Stanton
authors.forename: Ron C
authors.initials: RC
authors.lastname: Kelly
authors.forename: Adria
authors.initials: A
authors.lastname: Colletti
authors.forename: Y-H
authors.initials: YH
authors.lastname: Kiang
authors.forename: Meghan
authors.initials: M
authors.lastname: Langley
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Munson
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Peterson
authors.forename: John
authors.initials: J
authors.lastname: Roberts
authors.forename: Mary
authors.initials: M
authors.lastname: Wells
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry; D019817:Benzoic Acid / Q000737:chemistry; D052160:Benzothiazoles / Q000737:chemistry* / Q000493:pharmacokinetics*; D002934:Cinnamates / Q000737:chemistry; D003460:Crystallization; D018360:Crystallography, X-Ray; D008297:Male; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D052160:Benzothiazoles; D002934:Cinnamates; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D050916:TRPV Cation Channels; C029010:cinnamic acid; C037689:benzamide; D019817:Benzoic Acid; C411088:cinnamamide