title: A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys.
abstract: The farnesoid X receptor (FXR) belongs to one of the human nuclear receptor superfamilies that regulate gene transcription. FXR is widely expressed in liver, gall bladder, intestine, kidney, and adrenal glands. It serves as a key controller of bile acid homeostasis through its regulation of bile acid synthesis, conjugation, secretion, and absorption. FXR is also known to play a role in lipid regulation, triglyceride synthesis, and lipoprotein metabolism and clearance. We used a commercially available FXR agonist, GW4064, as a model compound to assess preclinical efficacy in two species (hamster and cynomolgus monkey). The crystalline GW4064, however, was found to have limited solubility, which resulted in poor oral bioavailability. This made it difficult to assess in vivo efficacy at the exposure levels desired. The physiochemical properties of GW4064 were assessed and both salt and self-emulsifying drug delivery system (SEDDS) formulation were developed and tested. The SEDDS formulation was found to greatly improve the oral bioavailability of GW4064, and permitted the evaluation of FXR agonist target efficacy.
authors.affiliation: Pfizer Global Research and Development, St. Louis Laboratories, Chesterfield, Missouri 63017, USA. Chiang.pochang@gene.com
authors.forename: Po-Chang
authors.initials: PC
authors.lastname: Chiang
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.forename: Sarbani
authors.initials: S
authors.lastname: Ghosh
authors.forename: Monique R
authors.initials: MR
authors.lastname: Heitmeier
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D007555:Isoxazoles / Q000494:pharmacology*; D008252:Macaca fascicularis; D008647:Mesocricetus; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D012995:Solubility; D053719:Tandem Mass Spectrometry; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064