The Use of BDDCS in Classifying the Permeability of Marketed Drugs

Abstract

We recommend that regulatory agencies add the extent of drug metabolism (i.e., ≥90% metabolized) as an alternate method in defining Class 1 marketed drugs suitable for a waiver of in vivo studies of bioequivalence. That is, ≥90% metabolized is an additional methodology that may be substituted for ≥90% absorbed. We propose that the following criteria be used to define ≥ 90% metabolized for marketed drugs: Following a single oral dose to humans, administered at the highest dose strength, mass balance of the Phase 1 oxidative and Phase 2 conjugative drug metabolites in the urine and feces, measured either as unlabeled, radioactive labeled or nonradioactive labeled substances, account for ≥ 90% of the drug dosed. This is the strictest definition for a waiver based on metabolism. For an orally administered drug to be ≥ 90% metabolized by Phase 1 oxidative and Phase 2 conjugative processes, it is obvious that the drug must be absorbed. This proposal, which strictly conforms to the present ≥90% criteria, is a suggested modification to facilitate a number of marketed drugs being appropriately assigned to Class 1.

Metabolism, Excretion, and Pharmacokinetics of [14C]INCB018424, a Selective Janus Tyrosine Kinase 1/2 Inhibitor, in Humans

“…In the current study, total recovery of administered radioactivity was 96% (74% in urine and 22% in feces) with Ͻ1% of the recovered dose excreted as parent drug, indicating that Ͼ99% of the administered dose was metabolized. Because metabolites of a compound that is stable in intestinal fluids must originate from absorbed drug (as indicated by Benet et al, 2008), results from this study strongly suggest that after an oral In some cases, structures with multiple designations represent stereoisomers (2-hydroxycyclopentyl, 3-hydroxycyclopentyl, and 3-oxocyclopentyl). The 2-hydroxycyclopentyl metabolites (M18 and M31) and 3-hydroxycyclopentyl metabolites (M7, M8, M16, and M27) may also be metabolized to form M37 and/or M38 (arrow not shown for viewing purposes).…”

In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor

“…Based on the limited aqueous solubility and high permeability, DTG is a Biopharmaceutics Drug Disposition Classification System class 2 drug (Benet et al, 2008(Benet et al, , 2011, where efflux transporters and metabolizing enzymes are predicted to be important in the drug's disposition. Indeed, in vitro studies show that DTG undergoes extensive metabolism and is a substrate for Pgp and BCRP, two transporters reported to influence the intestinal absorption and central nervous system penetration of HIV drugs (Kivisto et al, 2004).…”

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

“…Overall, the physicochemical features of BE are associated with a balance of limited passive permeability and hepatic metabolism and enhanced interaction with hepatic uptake as well as efflux transporters. Based on apparent correlation between intestinal permeability and extent of drug metabolism, the biopharmaceutics drug disposition classification system has been proposed (Wu and Benet, 2005;Benet et al, 2008Benet et al, , 2011Benet, 2009). Accordingly, the major route of elimination of high-permeability (class I and II) drugs is metabolism, predominantly cytochrome P450-mediated, whereas the major route of elimination for the poorly permeable (class III and IV) drugs is renal and/or BE of unchanged drug (Benet et al, 2011;Varma et al, 2012).…”