title: Leveraging BCS in Development: A Case Study.
abstract: In this work, we discuss leveraging the Biopharmaceutics Classification System (BCS) in the development of edivoxetine HCl, a selective norepinephrine reuptake inhibitor. First, the biopharmaceutical and in vivo data are presented and discussed. Solubility studies indicate that edivoxetine HCl meets the BCS "highly soluble" criteria. To determine permeability classifications, in vitro intestinal Caco-2 epithelial cell model with and without cyclosporin A (CsA), a common P-glycoprotein (P-gp) inhibitor, were conducted. Pharmacokinetic (PK) data obtained across phase 1 and 2 clinical studies where single and multiple doses range from the lowest to the highest strength are presented. Neither the Caco-2 nor the in vivo data on their own were sufficient to conclusively classify edivoxetine as highly permeable. However, collectively the data were utilized to support high permeability and consequently BCS1 classification of edivoxetine HCl. BCS1 classification was leveraged throughout development to assess the risk associated with not conducting relative bioavailability (RBA) studies and avoiding bioequivalence (BE) studies. Examples are presented where formulation changes were made between phase I (drug in capsule/drug in bottle formulations) and phase II (tablet) trials in addition to phase III (tablet) and commercial (smaller tablet) without having to conduct any in vivo comparability studies. For the first change, BCS was leveraged to avoid conducting a RBA study even before obtaining official BCS classification. For the later change, official BCS1 classification was relied upon to avoid conducting a BE study.
authors.affiliation: Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Cherokee Sue
authors.initials: CS
authors.lastname: Hoaglund Hyzer
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Butler University , Indianapolis, Indiana 46208, United States.
authors.forename: Hala M
authors.initials: HM
authors.lastname: Fadda
authors.affiliation: Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Jole O
authors.initials: JO
authors.lastname: Rodriguez
authors.affiliation: Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Aktham
authors.initials: A
authors.lastname: Aburub
mesh_terms: D001682:Biological Availability; D001702:Biopharmaceutics / Q000145:classification* / Q000379:methods; D018938:Caco-2 Cells / Q000378:metabolism; D002214:Capsules; D002626:Chemistry, Pharmaceutical / Q000379:methods; D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007408:Intestinal Absorption; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D012995:Solubility; D013607:Tablets
chemical_list: D002214:Capsules; D009025:Morpholines; D013607:Tablets; C568831:alpha-((5-fluoro-2-methoxyphenyl)methyl)-alpha-(tetrahydro-2H-pyran-4-yl)-2-morpholinemethanol; D010626:Phenylethyl Alcohol
keywords: BCS; biowaiver; edivoxetine HCl; permeability; solubility