I

II

III

IV

Class Food effect Drug - Drug interaction Efflux of transpoter

No effect on drugs because measure of the drugs are transporter substrates Increases peak time by delaying stomach emptying

This class of drugs metabolises in the intestline andliver. Drug Interaction occurs Primarily with transporterenzyme.

Inhibition of hepatic uptake transporter leads toIncrease in systemic drug concentration.

Inhibition of renal and hepatic transporter can lead toincreased systematic drug concentration

These Compounds readily pass throughG.I. membrane and allows both efflux and absorptive transporters to saturate. Class 1 compounds are substrate for both uptake and efflux transporter.

High Permeability allows to pass through the G.I. membrane & uptake will have no effect on the absorption however low solubility will limit the concentration at the enterocytes thereby preventing the saturation of efflux transporter

Class 3 & 4 will be unavailable in the gut due to good solubility.Since the influx of the compound will be rate limited by the absorptive transporter, the counter effect of the efflux transporter will not be saturated.

High Fat meals will decrease the extend of Class3 Compounds. Compounds of the Class 4 were found difficult to predict.

Increased extend of Class 2 Compound Peak time increases due to slowing of stomach emptying & decreases due to inhibition of efflux cycling

BIOPHARMACEUTICS DRUG DISPOSITION CLASSIFICATION SYSTEM (BDDCS) A RATIONAL MODIFICATION OVER FDA'S BIOPHARMACEUTICS CLASSIFICATION SYSTEM

BIOPHARMACEUTICS DRUG DISPOSITION CLASSIFICATION SYSTEM (BDDCS) A RATIONAL MODIFICATION OVER FDA'S BIOPHARMACEUTICS CLASSIFICATION SYSTEM

H.K. College of Pharmacy, Oshiwara, Jogeshwari (W), Mumbai-102.

Phale T., Borade A., Kanekar H., Mulay S., Khale A.

Abstract:The Biopharmaceutics Classification System (BCS) categorizes drugs which is explained through the below Fig a. Based on BCS classification, BDDCS can be classified which is explained through Fig b. BDDCS assist in predicting route of drug elimination, effect of efflux and absorptive transporters on oral drug absorption. The BDDCS also assist in the prediction of effect of transporter enzyme and drug-drug interaction potential. In BDDCS permeability component is replaced by metabolism component prove to be useful tool in predicting overall drug dispositions, effect of food and transporter.

The Biopharmaceutics Classification System (BCS) was developed for prediction of in-vivo pharmacokinetic

performance of drug products from measurements of permeability and Solubility. The BCS was developed

primarily in the context of immediate release (IR) solid oral dosage forms. BCS recommends method for

classification according to dosage form dissolution along with the solubility–permeability characteristics of the drug

product. Drug substances are classified in four classes of BCS.

INTRODUCTION:

Factors affecting BCS classification and their class boundaries

1) BCS based bio-waivers are not applicable for the Narrow therapeutic range drug

products & BCS based bio-waivers have limited application for the class II drugs and not

applicable for class III.2) Dosage form meant for absorption in the oral cavity e.g. sublingual or buccal tablets.3) Effects of food, absorptive transporters, efflux transporters, and routes of elimination

(renal/biliary) were important determinants of overall drug absorption and bioavailability for immediate release oral dosage forms, which are not considered in BCS

Factors affecting BDDCS:Fig.c Transporter effects on drug disposition by BCS class

1 Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of

cyclosporine with concomitant rifampin administration is markedly less than

predicted by hepatic enzyme induction. Clin.Pharmacol.Ther. 1992; 52:453–7.2. Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS:

transport ⁄ absorption ⁄elimination interplay and development of a Biopharmaceutics Drug Disposition Classification System. Pharm Res 2005; 22:11–23.

3. Food and Drug Administration. Guidance for Industry: WaiverofIn Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BiopharmaceuticsClassification System. Food and Drug Administration,Rockville, MD, 2000. Retrieved from http://www.fda.gov/cder/guidance/index.htm.

4. Lau YY, Okochi H, Huang Y, Benet LZ. Multiple transportersaffect the disposition of atorvastatin and its two active hydroxyl metabolites: application of in vitro and ex situ systems. J PharmacolExpTher 2006; 316:762–71.

5. Kataria M, Bhandari A. Biopharmaceutics drug disposition classification system. Int. Res. J. of Pharm. 2012, 3(3).

*The articles quoted here are only the key articles among several studied articles.

BCS /BDDCS AND REGULATORY GUIDANCES:

USFDA BCS Guidance proposed new boundaries for bio-waiver based on the underlyingphysiology of the GI tract. These include narrowing of the required pH range for solubilitymeasurement and reducing the high permeability requirement. New criteria was proposed for extending bio-waiver to BCS Class II and III drugs, as these are low solubility drugs henceincreasing the dose volume for solubility classification may be necessary.

European Medicines Agency (EMEA) has recently revised its bioequivalence guideline incontext to drugs exhibiting high permeability(BCS Class I drugs).

The EMEA Guideline has recognized the higher risks in making an inappropriate bio-waiverdecision for BCS Class 3 than BCS Class 1 drugs, including the possibility of site-specificabsorption, transporter interactions at the absorption site, excipient interaction with the active ingredient, and therapeutic risks.

Tools used in BDDCS:

The actual challenge for both BCS and BDDCS isto get the required in vitrodataformetabolism, solubility or permeability.However,there are some in silico methods for predictionof absorption, distribution, metabolism and excretion as followed, RANDOM FORESTSUPPORT VECTOR MACHINERECURSIVE PARTITIONINGALGORITHN WITH CHEM DRAW

Conclusion: In BDDCS permeability component is replaced by metabolism component prove to be useful tool in predicting overall drug dispositions, effect of food and transporter. Thus, the BDDCS expand the number of class 1 drug eligible of bio-waiver of in-vivo bioequivalence studies, and provide new insight for other classes.

References*:

ü BDDCS assist in predicting route of drug elimination, effect of efflux and absorptive transporters on oral drug absorption.

ü The BDDCS also assist in the prediction of effect of transporter enzyme and drug-drug interaction potential

üBDDCS is also useful in predicting where pharmacogeneticüvariants can yield meaningful drug disposition changesüPredict potential drug–drug interactions not tested in the drug approval process.üPredict the potential relevance of transporter–enzyme interplay.üPredict when transporter inhibition by uremic toxins may change hepatic

elimination.üPredict the brain disposition.ü Increase the eligibility of drugs for BCS Class 1 bio-waivers using measures of

metabolism.

USES OF BDDCS:

IN-VIVO

Table 1

Table 2

Table 4

Table 3

Tushar PhaleMob.: 9870629494E-mail : phaletushar@gmail.com

Fig.d Predictability of high-fat meal effects by BCS class Fig.e Predominant routes of drug elimination for drug substances by BCS class

Limitation of the BCS classification

Biological Drug Disposition Classification System (BDDCS)

Here the permeability criteria is changed with metabolism criteria, then it may be useful in predicting overall

drug disposition, including routes of drug elimination and the effects of efflux and absorptive transporters on

oral drug absorption, importance of food effects, and transporter effects on post absorption systemic drug

concentrations following oral and intravenous dosing known as Biopharmaceutics drug disposition

classification system (BDDCS). The drugs that have high permeability but poor metabolism are generally

hydrophilic molecules with low molecular weight are likely to be absorbed by active transport mechanisms.

Suggesting that drugs have extensive metabolism are highly absorbed. BDDCS using elimination criteria

may expand the number of Class 1 drugs eligible for a bio-waiver of in-vivo bioequivalence (BE) studies and

provide predictability of drug disposition profiles for Classes 2, 3, and 4 compounds.

H K I M S R

BCS BDDCS

ExamplesClass

I

II

III

IV

Description

High absorption and High dissolution

High absorption andPoor dissolution

High Variation in the rateand extent of drug absorption withrapid dissolution

Exhibit Poor and Variable bioavailability

Drug Dissolution Metoprolol, Diltiazem,Verapamil, Propranolol

Ketokonazole, Nifedipine,Itraconozole, MefenemicAcid

Hydrochlorthiazide, Taxol

Salvation rate

Penetration rate

Penetration rate

Rate Limiting Step

Class

Highly Soluble

Highly Permeable

Rapidly dissolving

The Highest dose strength is soluble in <

250ml water over the PH range of 1-7.5

When the extent of absorption in humans is

determined to be > 90% of administered dose

When > 85% of the labelled amount of drug

substance dissolves within 30 mins using

USP apparatus 1 or 2 in a volume of <

900 mlbuffer solution

Class Boundaries

I

II

III

IV

Class BCS BDDCS

It takes into account solubility and permeabilitycriteria to classify the drug compounds.

It takes into account solubility and metabolism criteria

It is less ambiguous

More no. of drug are available for biowaiver

It is applicable in condition where food and transporter interaction occurs.

It is more ambiguous

Less no.of drugs are available for biowaiver

It is not applicable in condition where food andtransporter interaction occurs.

Clomifene Citrate, Didanosine, Ethambutol

Fig.c Transporter effects on drug disposition by BCS class

IN-VIVO

Table 1

Table 4

Fig.d Predictability of high-fat meal effects by BCS class Fig.e Predominant routes of drug elimination for drug substances by BCS class

BCS BDDCS