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Pharmaceutical Research, Vol. 52, No. 3, March 2008 ( # 2007) DOI: 10.1007/s11095-007-9523-x
Commentary The Use of BDDCS in Classifying the Permeability of Marketed Drugs
Leslie Z. Benet,1,9 Gordon L. Amidon,2 Dirk M. Barends,3 Hans Lennerns,4 James E. Polli,5 Vinod P. Shah,6 Salomon A. Stavchansky,7 and Lawrence X. Yu8
Received September 4, 2007; accepted December 6, 2007; published online January 31, 2008
Abstract. We recommend that regulatory agencies add the extent of drug metabolism (i.e.,90% metabolized) as an alternate method in dening 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 for90% absorbed. We propose that the following criteria be used to dene90% 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 for90% of the drug dosed. This is the strictest denition for a waiver based on metabolism. For an orally administered drug to be90% 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 present90% criteria, is a suggested modication to facilitate a number of marketed drugs being appropriately assigned to Class 1.
KEY WORDS: BCS; BDDCS; bioequivalence; elimination pathways.
INTRODUCTION
Based on the work of Amidon and colleagues (1)theFDA promulgated the guidance for waiver of in vivo bioavailability and bioequivalence testing of immediate-release solid dosage forms for drugs that are Biopharmaceutics Classication System (BCS) Class 1 high-solubility, high-permeability, when such
drug products also exhibit rapid dissolution (2). This hallmark guidance reects the interest of the FDA in decreasing the regulatory burden utilizing a science-led approach.
There is great interest world wide in the BCS and particularly in its use to assure bioequivalence of drug products in developing countries where the infrastructure is usually not available to carry out denitive human bioequi-valence studies. The major difculty in assigning drugs to Class 1, where such drug products would then be amenable to waiver of in vivo bioequivalence, is the determination of permeability. In the FDA guidance...