319 Prediction System

Pre-clinical data used to predict clinical absorption and clearance

Calculated chemical properties (solubility, pKa, LogP, LogD, MW, PSA, HBD, HBA), permeability assays (Caco-2, MDKC-LE), transporter substrate assays, drug metabolism substrate assays

Biopharmaceutics Classification System (BCS)

Predicts potential formulation problems for oral absorption and it is used to judge generic drug formulations

BCS Class 1

Oral absorption is not solubility or permeability limited. Formulation is simple.

BCS Class 2

Oral Absorption is solubility limited but is not permeability limited. May need solubility enhancer like a salt form.

BCS Class 3

Oral absorption is not solubility limited but is permeability limited. May need permeability enhancer excipient.

BCS Class 4

Oral is solubility and permeability limited. Challenging formulation may need alternate route of administration.

BCS Class 1 Extent of Permeability

Caco-2 cell experiment compared to known molecules of low, moderate, and high permeability

BCS Class 1 Extent of Solubility

Highest single therapeutic dose is completely soluble in 250ml or less of aqueous media at pH 1.2, 4.5, and 6.8 at 37C.

BCS Class 1 Rate of solubility

>85% of dose dissolved in <30 minutes

BCS Class 1 and 2 primary elimintation

By metabolism (high intestinal permeability)

BCS Class 3 and 4 Primary elimintation

Unchanged in urine or bile (low intestinal permeability)

Biopharmaceutics Drug Disposition Classification System

Adds route of elimination to original BCS

BDDCS Class 1

Dominant route of elimination is metabolism (>70%) Oral absorption is not limited

BDDCS Class 2 

Dominant route of elimination is metabolism (>70%). Oral absorption is solubility limited. 

BDDCS Class 3

Dominant route of elimination is renal/bile of unmetabolized drug. Oral absorption is permeability limited.

BDDCS Class 4

Dominant route of elimination is renal/bile of unmetabolized drug. Oral absorption is solubility limited and permeability limited.

Purpose of BDDCS 

Is to predict drug disposition and potential drug-drug interactions (DDI) in the intestine and the liver. If a drug is highly metabolized DDI are possible. 

Purpose of ECCs

To include absorption and clearance by all the major mechanisms like permeability (diffusion), metabolism enzymes, transporters, and by organ (liver, kidney). Adds onto original BCS and BDDCS

ECCs Class 1A

Absorption by diffusion in enterocyte and hepatocyte. MW<400. Cleared by metabolism. Both permeable and soluble. Acids/Zwitterions. High permeability. Tend to be metabolized by UGT, CYP2C, Esterases. Excreted as metabolites

ECCs Class 1B

MW>400. Absorption by hepatic uptake by OATP1B1 and OAT1B3. Cleared by metabolism. Acids/Zwitterions. High permeability. Excreted in bile/urine as metabolites. 

ECCs Class 2

Small and large molecules. Absorbed by diffusion in enterocyte and hepatocyte. Cleared by metabolism. Bases/Neutrals. High permeability. Metabolized by CYP3A4, UGT, CYP2C. Clearance is well predicted by human liver microsomes and human hepatocytes. Excreted in bile or urine as metabolites

Drug Examples of ECCS Class 1A

Diclofenac, Tolbutamide, Mycophenolic Acid, Gemfibrozil, Rosiglitazone

Drug examples of ECCS class 2 drugs

Midazolam, propranolol, nifedipine, verapamil, Quinidine, DXM, Bupropion, Clozapine, Cyclosporine, Digoxin

Drug examples of class 3A drugs 

Oseltamivir, Furosemide 

Drug examples of Class 3B drugs

Statins

Drug examples of ECCs class 4 

Irinotecan, famotidine, cimetidine, Digoxin

ECCs Class 3A

Absorption by diffusion. <400 MW. Renal Clearance by BCRP, MRP2, P-gp, OAT1 and OAT3. Acids/Zwitterions. Low permeability. Excreted in urine as unchanged drug. Absorption is likely incomplete. Limited by intestinal efflux transporters. Enhanced by intestinal active uptake transporters (MCTs, PEP1, System L)

ECCS Class 3B

MW>400. Absorption by diffusion. Hepatic uptake or renal clearance by OAT1, OAT3. Acids/Zwitterions. Lower permeability.  Limited by intestinal efflux transporters. Enhanced by intestinal active uptake transporters (MCTs, PEP1, System L). Excreted as unchanged drug. Absorption likely incomplete.

ECCs Class 4

Large or small molecules. Absorption by hepatic uptake, OCT or OCTN. Renal clearance by OAT1, OAT3, OCT2, and MATE. P-gp, MATE1/2K efflux transporters. Bases/Neutrals. Low permeability. Excreted as unchanged drug.

Zwitterion

Molecule that contains both acidic and basic functional groups

OCT

Organic Cation Transporters 

OAT

Organic Anion transporter

Pgp, MDR1, BCRP

Neutral molecule transporters

Contributors to Absorption and Clearance

Diffusion, transporters, blood and fluid flow direction, plasma protein binding

Oral dosage to small intestine —→ Diffusion to enterocytes —→ diffusion to hepatocytes —→ diffusion to blood (pre systemic, vein to liver)—→ to heart for systemic circulation —→ to kidney for elimination or to bile for elimination