BDDCS Applied to Over 900 Drugs

Abstract

Abstract. Here, we compile the Biopharmaceutics Drug Disposition Classification System (BDDCS) classification for 927 drugs, which include 30 active metabolites. Of the 897 parent drugs, 78.8% (707) are administered orally. Where the lowest measured solubility is found, this value is reported for 72.7% (513) of these orally administered drugs and a dose number is recorded. The measured values are reported for percent excreted unchanged in urine, LogP, and LogD 7.4 when available. For all 927 compounds, the in silico parameters for predicted Log solubility in water, calculated LogP, polar surface area, and the number of hydrogen bond acceptors and hydrogen bond donors for the active moiety are also provided, thereby allowing comparison analyses for both in silico and experimentally measured values. We discuss the potential use of BDDCS to estimate the disposition characteristics of novel chemicals (new molecular entities) in the early stages of drug discovery and development. Transporter effects in the intestine and the liver are not clinically relevant for BDDCS class 1 drugs, but potentially can have a high impact for class 2 (efflux in the gut, and efflux and uptake in the liver) and class 3 (uptake and efflux in both gut and liver) drugs. A combination of high dose and low solubility is likely to cause BDDCS class 4 to be underpopulated in terms of approved drugs (N=53 compared with over 200 each in classes 1-3). The influence of several measured and in silico parameters in the process of BDDCS category assignment is discussed in detail.KEY WORDS: BDDCS; biowaiver; dose number; extent of metabolism; permeability rate.In 2005, Wu and Benet (1) introduced the Biopharmaceutics Drug Disposition Classification System (BDDCS). Wu and Benet recognized that there was a very strong correlation between the intestinal permeability rate and the extent of metabolism. For example, Benet et al. (2) noted that for the 29 drugs and endogenous substances for which human jejunal permeability rate measurements were available, there was an excellent correlation between these permeability rate measurements and the extent of drug metabolism in humans. Fourteen of the 16 drugs exhibiting human intestinal permeability rates greater than metoprolol were extensively metabolized, while 11 of 12 drugs showing permeability rates less than metoprolol were poorly metabolized. Two drugs showing disparity between the permeability rate and metabolism, cephalexin and losartan, exhibit permeability rates that differ by no more than 16% from metoprolol (2). Since the coefficients of variation for the human permeability parameters range from 29% to 130%, these borderline compounds may in fact also have followed the correlation. The correlation between the extent of metabolism and human intestinal jejunal permeability was markedly better than that observed for intestinal jejunal permeability and partition coefficient by Takagi et al. (3), who noted that Log P measured and calculated correctly predict high versus low permeability only about two thir...

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

“…For consistency, we relied primarily upon two sources of information for the BCS classification: Kasim et al (5), using their LogP-based estimates for our predictions of drug permeability, and Wu and Benet (7). For those several compounds that were not contained within those two references, other published values were used (3,4,6,76). Despite recognized diversity in some of the values across these various information sources, we concluded that since the magnitude of differences was small relative to the overall strength of the trends that were observed, any error that may have been introduced by the selection of publications would not influence the conclusions derived from our comparison.…”

Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies

“…For the compounds studied here, a thorough understanding of the involvement of uptake transporters and adequate data for PBPK modeling might be useful in improving prediction accuracy. Recent development of the Biopharmaceutics Drug Disposition Classification System (BDDCS) provides a basis for a qualitative prediction of the importance of transporters in the drug disposition [35]. As PBPK modeling advances to include the quantitative prediction of active transport in hepatic uptake and biliary secretion and indeed in intestinal absorption, BDDCS can help to prioritize which in vitro investigations should be conducted and to aid in the selection of mechanistic models.…”

Pluronic F127 as a suitable carrier for preparing the imatinib base solid dispersions and its potential in development of a modified release dosage forms

“…In aqueous media, imatinib base is characterized by poor solubility (0.01 mg mL -1 ) [1]. However, the mesylate salt of imatinib, which exists as a polymorph with two principal forms, [2,3] is very soluble in media at pH values B5.5, but in neutral and alkaline aqueous buffers is poorly soluble or insoluble [4]. Therefore, imatinib mesylate belongs to Class 2 of Biopharmaceutical Classification System (BCS) with a solubility of 1 mg mL -1 determined at pH 7.4 [4].…”

“…However, the mesylate salt of imatinib, which exists as a polymorph with two principal forms, [2,3] is very soluble in media at pH values B5.5, but in neutral and alkaline aqueous buffers is poorly soluble or insoluble [4]. Therefore, imatinib mesylate belongs to Class 2 of Biopharmaceutical Classification System (BCS) with a solubility of 1 mg mL -1 determined at pH 7.4 [4]. After oral administration, especially of the conventional dosage forms, imatinib mesylate is not absorbed to the same extent, when it passes the upper small intestine, where its absorption is the maximum.…”