Leveraging BCS in Development: A Case Study.
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.
['Hoaglund Hyzer|Cherokee Sue|CS|', 'Fadda|Hala M|HM|', 'Rodriguez|Jole O|JO|', 'Aburub|Aktham|A|']
D001682:Biological Availability D001702:Biopharmaceutics D018938:Caco-2 Cells D002214:Capsules D002626:Chemistry, Pharmaceutical D017321:Clinical Trials, Phase I as Topic D055808:Drug Discovery D006801:Humans D007408:Intestinal Absorption D009025:Morpholines D010626:Phenylethyl Alcohol D012995:Solubility D013607:Tablets
BCS edivoxetine HCl solubility permeability biowaiver