title: Investigation of clinical pharmacokinetic variability of an opioid antagonist through physiologically based absorption modeling.
abstract: Identifying the source of inter- and/or intrasubject variability in pharmacokinetics (PK) provides fundamental information in understanding the pharmacokinetics-pharmacodynamics relationship of a drug and project its efficacy and safety in clinical populations. This identification process can be challenging given that a large number of potential causes could lead to PK variability. Here we present an integrated approach of physiologically based absorption modeling to investigate the root cause of unexpectedly high PK variability of a Phase I clinical trial drug. LY2196044 exhibited high intersubject variability in the absorption phase of plasma concentration-time profiles in humans. This could not be explained by in vitro measurements of drug properties and excellent bioavailability with low variability observed in preclinical species. GastroPlus™ modeling suggested that the compound's optimal solubility and permeability characteristics would enable rapid and complete absorption in preclinical species and in humans. However, simulations of human plasma concentration-time profiles indicated that despite sufficient solubility and rapid dissolution of LY2196044 in humans, permeability and/or transit in the gastrointestinal (GI) tract may have been negatively affected. It was concluded that clinical PK variability was potentially due to the drug's antagonism on opioid receptors that affected its transit and absorption in the GI tract.
authors.affiliation: Small Molecule Design & Development, Lilly Technology Center, Eli Lilly and Company, Indianapolis, Indiana 46221, USA. ding_xuan@lilly.com
authors.forename: Xuan
authors.initials: X
authors.lastname: Ding
authors.forename: Minxia
authors.initials: M
authors.lastname: He
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kulkarni
authors.forename: Nita
authors.initials: N
authors.lastname: Patel
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000818:Animals; D001596:Benzylamines / Q000737:chemistry / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004285:Dogs; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009292:Narcotic Antagonists / Q000737:chemistry / Q000493:pharmacokinetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D010539:Permeability; D051381:Rats; D020318:Rats, Long-Evans; D012995:Solubility; D055815:Young Adult
chemical_list: D001596:Benzylamines; C586667:LY2196044; D009292:Narcotic Antagonists; D009536:Niacinamide
keywords: drug effects; oral absorption; permeability; pharmacokinetics; simulations