The FDA Should Eliminate the Ambiguities in the Current BCS Biowaiver Guidance and Make Public the Drugs for Which BCS Biowaivers Have Been Granted

129

119

ABSTRACT. There is a growing need for highly accurate in silico and in vitro predictive models to facilitate drug discovery and development. Results from in vitro permeation studies across the Caco-2 cell monolayer are commonly used for drug permeability screening in industry and are also accepted as a surrogate for human intestinal permeability measurements by the US FDA to support new drug applications. Countless studies carried out in this cell line with published permeability measurements have enabled the development of many in silico prediction models. We identify several common cases that illustrate how using Caco-2 permeability measurements in these in silico and in vitro predictive models will not correlate with human intestinal permeability and will further lead to inaccuracies in these models. We provide guidelines and recommendations for improving these models to more accurately predict clinically relevant information, thereby enhancing the drug discovery, development, and regulatory approval processes.

Section: Introductionmentioning

confidence: 69%

Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements

Larregieu

Benet

2013

129

119

“…As noted above, BDDCS predictions and classification are based on the intestinal permeability rate, not the extent of permeability. There is some ambiguity with respect to the basis for BCS, as reviewed by Benet and Larregieu (6). The initial permeability studies of Amidon, Lennernäs, and colleagues (5,8), as summarized by Takagi et al (3), show a good correlation between human intestinal permeability rate and the extent of absorption, as detailed earlier in the first paragraph of this paper.…”

Section: Bddcs Versus Bcsmentioning

confidence: 86%

BDDCS Applied to Over 900 Drugs

Benet

Broccatelli

Oprea

2011

555

529

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...

“…Today, the science and validity of the BCS are well established, and many Electronic supplementary material The online version of this article (doi:10.1208/s12248-012-9350-9) contains supplementary material, which is available to authorized users. biowaiver extensions have been proposed by the scientific community and some have been approved by regulatory bodies (8)(9)(10)(11). Note: a dichotomy in nomenclature exists between WHO and US documents wherein bioequivalence in WHO terminology refers to a comparative blood level (pharmacokinetic studies).…”

Section: Introductionmentioning

confidence: 99%

Toward Global Standards for Comparator Pharmaceutical Products: Case Studies of Amoxicillin, Metronidazole, and Zidovudine in the Americas

Löbenberg

Chacra

Stippler

et al. 2012

Abstract. This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.