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

HKIMSR

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

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

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.

INTRODUCTION:
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 solubilitypermeability characteristics of the drug product. Drug substances are classified in four classes of BCS.

USES OF BDDCS:
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 BDDCS is also useful in predicting where pharmacogenetic variants can yield meaningful drug disposition changes Predict potential drugdrug interactions not tested in the drug approval process. Predict the potential relevance of transporterenzyme interplay. Predict when transporter inhibition by uremic toxins may change hepatic elimination. Predict the brain disposition. Increase the eligibility of drugs for BCS Class 1 bio-waivers using measures of metabolism.
Class BCS
It takes into account solubility and permeability criteria to classify the drug compounds. It is more ambiguous

Class

Description High absorption and High dissolution

Rate Limiting Step Drug Dissolution

Examples Metoprolol, Diltiazem, Verapamil, Propranolol

II

High absorption and Poor dissolution High Variation in the rate and extent of drug absorption with rapid dissolution Exhibit Poor and Variable bioavailability

Salvation rate

Ketokonazole, Nifedipine, Itraconozole, Mefenemic Acid Clomifene Citrate, Didanosine, Ethambutol Hydrochlorthiazide, Taxol

III

Penetration rate

BDDCS
It takes into account solubility and metabolism criteria

IV

Penetration rate

I II III

Table 1
Factors affecting BCS classification and their class boundaries

It is less ambiguous

Less no.of drugs are available for biowaiver

More no. of drug are available for biowaiver

Class
Highly Soluble

Class Boundaries
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

Highly Permeable

IN-VIVO

IV

It is not applicable in condition where food and transporter interaction occurs.

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

Table 3

BCS /BDDCS AND REGULATORY GUIDANCES:

USFDA BCS Guidance proposed new boundaries for bio-waiver based on the underlying physiology of the GI tract. These include narrowing of the required pH range for solubility measurement 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 hence increasing the dose volume for solubility classification may be necessary. European Medicines Agency (EMEA) has recently revised its bioequivalence guideline in context to drugs exhibiting high permeability(BCS Class I drugs). The EMEA Guideline has recognized the higher risks in making an inappropriate bio-waiver decision for BCS Class 3 than BCS Class 1 drugs, including the possibility of site-specific absorption, transporter interactions at the absorption site, excipient interaction with the active ingredient, and therapeutic risks.

Rapidly dissolving

substance dissolves within 30 mins using USP apparatus 1 or 2 in a volume of < 900 mlbuffer solution

Table 2

Limitation of the BCS classification

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

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 prediction of absorption, distribution, metabolism and excretion as followed, RANDOM FOREST SUPPORT VECTOR MACHINE RECURSIVE PARTITIONING ALGORITHN WITH CHEM DRAW

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.

BCS

BDDCS

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 biowaiver of in-vivo bioequivalence studies, and provide new insight for other classes.

References*:
Factors affecting BDDCS:
Fig.c Transporter effects on drug disposition by BCS class Fig.d Predictability of high-fat meal effects by BCS class Fig.e Predominant routes of drug elimination for drug substances by BCS class

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; 52:4537. 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; 22:1123. 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; 316:76271. 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.

Class

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

Drug - Drug interaction

Efflux of transpoter

I II III IV

These Compounds readily pass through This class of drugs metabolises in the intestline and liver. Drug Interaction occurs Primarily with transporter G.I. membrane and allows both efflux and absorptive transporters to saturate. Class 1 compounds are substrate for enzyme. both uptake and efflux transporter. Inhibition of hepatic uptake transporter leads to Increase in systemic drug concentration. 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 there by 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.

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

High Fat meals will decrease the extend of Class 3 Compounds. Compounds of the Class 4 were found difficult to predict.

Inhibition of renal and hepatic transporter can lead to increased systematic drug concentration

Table 4

Tushar Phale Mob.: 9870629494 E-mail : phaletushar@gmail.com

Table 1

IN-VIVO

BCS

BDDCS

Fig.c

Transporter effects on drug disposition by BCS class

Fig.d

Predictability of high-fat meal effects by BCS class

Fig.e

Predominant routes of drug elimination for drug substances by BCS class

Table 4