title: Selection of oral bioavailability enhancing formulations during drug discovery.
abstract: The objective of this paper was to identify oral bioavailability enhancing approaches for a poorly water-soluble research compound during drug discovery stages using minimal amounts of material.   LCQ789 is a pBCS (preclinical BCS) Class II compound with extremely low aqueous solubility (<1 µg/mL) and high permeability, therefore, resulting in very low oral bioavailability in preclinical species (rats and dogs). A number of solubility and/or dissolution enhancing approaches including particle size reduction, solid dispersions, lipid-based formulations and co-crystals, were considered in order to improve the compound's oral bioavailability. High-Throughput Screening (HTS) and in silico modeling (GastroPlus™) were utilized to minimize the compound consumption in early discovery stages. In vivo evaluation of selected physical form and formulation strategies was performed in rats and dogs. Amongst the formulation strategies, optimized solid dispersion and lipid-based formulation provided significant improvement in drug dissolution rate and hence, oral bioavailability. In addition, a significant impact of physical form on oral bioavailability of LCQ789 was observed. In conclusion, a thorough understanding of not only the formulation technique but also the physical form of research compounds is critical to ensure physical stability, successful pharmacokinetic (PK) profiling and early developability risk assessment.
authors.affiliation: Astrazeneca Pharmaceuticals, Waltham, USA.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zheng
authors.forename: Akash
authors.initials: A
authors.lastname: Jain
authors.forename: Dimitris
authors.initials: D
authors.lastname: Papoutsakis
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Dannenfelser
authors.forename: Riccardo
authors.initials: R
authors.lastname: Panicucci
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Garad
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D055808:Drug Discovery / Q000379:methods*; D008055:Lipids / Q000737:chemistry*; D010316:Particle Size; D010539:Permeability; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D012995:Solubility
chemical_list: D004337:Drug Carriers; C571349:LCQ789; D008055:Lipids; D011720:Pyrazoles; D011744:Pyrimidinones