title: pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery.
abstract: The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin-Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the fraction absorbed in human (Fa). Receiver operating characteristic (ROC) curve analysis was utilized to define the permeability class boundary. At permeability ≥ 5 × 10(-6) cm/s, the accuracy of predicting Fa of ≥ 0.90 was 87%. Also, this cutoff showed more than 80% sensitivity and specificity in predicting the literature permeability classes (BCS), and the metabolism classes (BDDCS). The equilibrium solubility of a subset of 49 drugs was measured in pH 1.2 medium, pH 6.5 phosphate buffer, and in FaSSIF medium (pH 6.5). Although dose was not considered, good concordance of the measured solubility with BCS and BDDCS solubility class was achieved, when solubility at pH 1.2 was used for acidic compounds and FaSSIF solubility was used for basic, neutral, and zwitterionic compounds. Using a cutoff of 200 μg/mL, the data set suggested a 93% sensitivity and 86% specificity in predicting both the BCS and BDDCS solubility classes. In conclusion, this study identified pH-dependent permeability and solubility criteria that can be used to assign provisional biopharmaceutics class at early stage of the drug discovery process. Additionally, such a classification system will enable discovery scientists to assess the potential limiting factors to oral absorption, as well as help predict the drug disposition mechanisms and potential drug-drug interactions.
authors.affiliation: Pfizer Global Research and Development, Pfizer Inc, Groton, Connecticut 06340, United States.
authors.forename: Manthena V
authors.initials: MV
authors.lastname: Varma
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.forename: Paul
authors.initials: P
authors.lastname: Nkansah
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Rotter
authors.forename: Carrie
authors.initials: C
authors.lastname: Whitney-Pickett
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: Michael
authors.initials: M
authors.lastname: Cram
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Fenner
authors.forename: Ayman F
authors.initials: AF
authors.lastname: El-Kattan
mesh_terms: D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D002460:Cell Line; D004285:Dogs; D055808:Drug Discovery / Q000379:methods; D006863:Hydrogen-Ion Concentration; D010539:Permeability; D012995:Solubility