title: Investigation of Dose-Dependent Factors Limiting Oral Bioavailability: Case Study With the PI3K-δ Inhibitor.
abstract: It is understood that a potential issue for drugs with poor aqueous solubility is low oral absorption. If oral exposure issues arise when working with a low solubility drug candidate, the common action is to rely on enabling formulations to solve the issue. However, this approach becomes troublesome in the pre-clinical setting where compound absorption, distribution, metabolism, excretion properties are suboptimal and more factors limiting bioavailability may be at play. A narrow focus on solubility enhancement without a full understanding of compound absorption, distribution, metabolism, excretion properties can produce data that cloak the actual phenomena driving exposure. Compound 1 is a potent and selective PI3Kdelta inhibitor with poor aqueous solubility. In a pharmacokinetic study on dogs, exposure was found to be less than dose-linear. Besides the solubility, further investigations were conducted to identify other factors limiting oral exposure. It was observed that these limiting factors are dose dependent. Results from modeling pharmacokinetic under low-dose conditions suggest that exposure is significantly limited by metabolism and no exposure improvements should be expected from enabled formulations. Furthermore, enabling formulations are expected to exert a beneficial influence at higher doses. An in vivo test was conducted in dogs to verify this phenomenon.
authors.affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080. Electronic address: Chiang.pochang@gene.com.
authors.forename: Po-Chang
authors.initials: PC
authors.lastname: Chiang
authors.affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sutherlin
authors.affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, California 94080.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human
keywords: bioavailability; metabolites; oral exposure; pharmacokinetic; solubility