The Role of BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) in Drug Development

Benet, Leslie Z.

doi:10.1002/jps.23359

Cited by 256 publications

(184 citation statements)

References 34 publications

(51 reference statements)

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“…Finally, low permeability compounds were highly represented as substrates of hepatic basolateral uptake transporters (32). Importantly, their data indicate that in vitro permeability rate can be used as a surrogate for extent of metabolism for new molecular entities (NMEs) when clinical data is unavailable, as has been proposed by our laboratory (31,33,34). Specifically, compounds with permeability rates equal to or exceeding a standard, e.g., metoprolol, are likely extensively metabolized in vivo in humans, while those with permeability rates lower than the standard are likely eliminated primarily as unchanged drug in either the bile or the urine.…”

Section: Introductionmentioning

confidence: 85%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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Abstract. Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

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Section: Introductionmentioning

confidence: 85%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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“…Class I: high solubility, high permeability: generally very well-absorbed compounds Class II: low solubility, high permeability: exhibits dissolution rate-limited absorption Class III: high solubility, low permeability: exhibits permeability-limited absorption Class IV: low solubility, low permeability: very poor oral bioavailability A complementary classification system was proposed by Wu and Benet (7,8). They recognized that drugs exhibiting high permeability are generally extensively metabolized, while poorly permeable compounds are primarily eliminated as unchanged drug in the bile and urine.…”

Section: Introductionmentioning

confidence: 99%

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

Papich

Martinez

2015

AAPS J

101

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Abstract. The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of Bwhat if^scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug's F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or paracellular transporters). Although there are limitations to the approach used in this study, the results of our assessment strongly suggest that the human BCS classification system requires substantial modification before it can be reliably applied to dogs.

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“…Ert is a poorly soluble drug that falls under BCS class II [10]. Currently, Ert is recommended to be administered on an empty stomach to decrease the potential side effects of excessive absorption caused by dietary influences; however, this can undermine the convenience of drug administration [12,13].…”

Section: Discussionmentioning

confidence: 99%

“…Ert has a maximal solubility of approximately 0.4 mg/mL at pH of approximately 2 [8]. It belongs to the Biopharmaceutical Classification System (BCS) class II drugs, which are characterized by low solubility and high permeability [9,10]. Peak plasma concentrations and the area under the drug concentration-time curve (AUC) vary between patients orally administered with the same amount of Tarceva V R .…”

Section: Introductionmentioning

confidence: 99%

Nanoparticulation improves bioavailability of Erlotinib

Yang

Shin

Park

et al. 2017

Drug Development and Industrial Pharmacy

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Objectives: Nanoparticulation using fat and supercritical fluid (NUFS TM ) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFS TM could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert). Methods: NUFS-Ert was prepared using NUFS TM technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed. Results: NUFS-Ert nanoparticles had an average size of 250 nm and were stable for 2 months at 40 C, 4 C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva V R . In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva V R . The relative bioavailability of NUFS-Ert compared with that of Tarceva V R was 550% and the ratio of the area under the concentration-time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva V R . Conclusions: NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva V R .ARTICLE HISTORY

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The Role of BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) in Drug Development

Cited by 256 publications

References 34 publications

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

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

Nanoparticulation improves bioavailability of Erlotinib

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