bcs and bddcs

BCS and BDDCSLeslie Z. Benet, Ph.D.

Department of Biopharmaceutical Sciences

University of California, San Francisco

EUFEPS & COST B2 ConferenceBioavailability and Bioequivalence:

Focus on Physiological Factors and Variability

Athens October 1, 2007

DISCLAIMER

As Amin Rostami-Hodjedan said, I claim I am nota modeler (even though Im not prejudice and some

of my best friends are modelers). Amin said mysimplified approaches are also models. I agree.

I develop simplified systems because I believe, as Isaid in the 1984 Preface, to which Amin referred,that what we believe today, upon which we base

our models, may not be true and that in a numberof cases we are adding complexity to models forwhich the basic assumptions may not be correct.

All EUFEPS COST B2 attendees will be familiar with theFDAs Biopharmaceutics Classification System (BCS)

The core idea in the BCS is that an in vitro transport model,centrally embracing permeability and solubility, withqualifications related to pH and dissolution, may qualify fora waiver of in vivo bioequivalence studies.

The objective of the BCS is to: predict in vivoperformance of drug products from in vitro measurementsof permeabilty and solubility.

However, we believe that the framework of the BCS canserve the interests of the earliest stages of discoveryresearch in predicting the absorption/disposition of NMEs.

High Solubility Low Solubility

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Amidon et al., Pharm Res 12: 413-420, 1995

CarbamazepineCyclosporineDigoxinKetoconazoleTacrolimus

AcetaminophenPropranololMetoprololValproic acid

CimetidineRanitidine

ChlorothiazideFurosemideMethotrexate

Biopharmaceutical Classification


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Amidon et al., Pharm Res 12: 413-420, 1995

Class 2Low SolubilityHigh Permeability

Class 1High SolubilityHigh PermeabilityRapid Dissolution

Class 3High SolubilityLow Permeability

Class 4Low SolubilityLow Permeability

Biopharmaceutical Classification

BCS High Solubility Criteria

A drug substance is consideredhighly soluble when the highestdose strength is soluble in 250 ml orless of aqueous media over a pHrange of 1-7.5 at 37C.

BCS High Permeability Criteria

A drug substance is considered tobe highly permeable when theextent of absorption in humans isdetermined to be 90% of anadministered dose based on a massbalance determination or incomparison to an i.v. reference dose


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Class 1 Abacavir Acetaminophen Acyclovirb Amiloride S,I

Amitryptyline S,I Antipyrine Atropine Buspirone c Caffeine Captopril Chloroquine S,I

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Dilt iazem S,I Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol Fluoxetine I

Glucose

Imipramine I Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S Lidocaine I Lomefloxacin Meperidine Metoprolol Metronida zole MidazolamS,I Minocycline Misoprostol Nifedi pine S Phenobarbital Phenylalanine Prednisolone Primaquine S Promazine Propranolol I Quinidine S,I Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I Ator vastatin S, I Azithromycin S ,I

Carbamazepine S,I Carvedilol Chlorpromazine I Cisapride S

Ciprofloxacin S Cyclosporine S, I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin S,I Flurbiprofen Glipizide Glyburide S,I Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole S,I Ketoconazole I Lansoprazole I Lovastatin S,I Mebendazole Naproxen Nelfinavir S,I

Nifedi pine S Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxi cam Raloxifene S Ritonavir S,I Saquinavir S,I Sirolimus S Spironolactone I Tacrolimus S,I Talinolol S

Tamoxifen I Terfenadine I Warfarin

Wu and Benet, Pharm Res 22:11-23 (2005)

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Class 3 Acyclovir Amiloride S,I Amoxicillin S,I Atenolol Atropine Bis phosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin S,I

Famoti dine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlor othiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Wu and Benet, Pharm Res 22:11 -23 (2005)


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Class 1Metabolism

Class 3Renal & BiliaryElimination ofUnchanged Drug

Class 4Renal & BiliaryElimination ofUnchanged Drug

Major Routes of Drug Elimination

Class 2Metabolism

What are the Implications of this StrongCorrelation between Permeability and Metabolism?

If you know the intestinal absorption (or morelikely a surrogate as Caco-2 permeability) of anNME, you can predict whether the major routeof elimination of the NME will be metabolism.

Note that the permeability parameter does notpredict the ability for the NME to enter the liver/hepatocytes (since a number of non-metabolizedClasses 3 & 4 compounds will be excreted in thebile), but rather the access to the metabolicenzymes within the hepatocytes.

Biopharmaceutics Drug Disposition Classification System

BDDCSHigh Solubility Low Solubility

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mClass 2Low SolubilityExtensive Metabolism

Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and 70% Metabolism for Biowaiver )

Class 3High SolubilityPoor Metabolism

Class 4Low SolubilityPoor Metabolism


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Class 1 Abacavir Acetaminophen Acyclovir b Amiloride S,I

Amitryptyline S,I Antipyrine Atropine Buspirone c Caffeine

Captopril Chloroquine S,I

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Dilt iazem S,I Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol Fluoxetine I

Glucose

Imipramine I Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S Lidocaine I Lomefloxacin Meperidine Metoprolol Metronida zole MidazolamS,I Minocycline Misoprostol Nifedi pine S Phenobarbital Phenylalanine Prednisolone Primaquine S Promazine Propranolol I Quinidine S,I Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I Ator vastatin S, I Azithromycin S ,I

Carbamazepine S,I Carvedilol Chlorpromazine I Cisapride S

Ciprofloxacin S Cyclosporine S, I Danazol Dapsone Diclofenac Diflunisal

Digoxin S Erythromycin S,I Flurbiprofen Glipizide Glyburide S,I Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole S,I Ketoconazole I Lansoprazole I Lovastatin S,I

Mebendazole Naproxen Nelfinavir S,I

Nifedi pine S Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxi cam Raloxifene S Ritonavir S,I Saquinavir S,I Sirolimus S Spironolactone I Tacrolimus S,I

Talinolol S

Tamoxifen I Terfenadine I Warfarin

BDDCS is a modification of the FDAsBiopharmaceutics Classification System.BDDCS was developed to address DDIs

and transporter-enzyme interplay,thereby providing a road map fordesigning preclinical and Phase 1

clinical studiesHowever, BDDCS may also be useful injustifying Class 1 status for marketed

drug products, increasing the number ofdrug products eligible for a waiver of in

vivo bioequivalence studies.

Many of you have heard Prof. Gordon Amidondiscuss the $20 M of human studies that he and

Prof. Hans Lennernas had run to determine theabsorption of a group of ~30 drugs that served as abasis for using metoprolol as the cut-off marker for

absorption greater than 90%

In a late 2006 published paper (Takagi et al., Mol.Pharm., 3:631-643, 2006) the human permeability

numbers for 29 reference drugs are compiled in aJournal publication, giving all of us the opportunityto test various permeability surrogates against the

experimental human values.

Reference Drugs -Methyldopa Amoxicillin Antipyrine Atenolol Carbamazapine Cephalexin Cimetidine Creatinine Desipramine D-Glucose Enalapril Enalaprilat Fluvastatin Furosemide Hydrochlorothiazide

Ketoprofen Levodopa Lisinopril L-Leucine Losartan Metoprolol Naproxen Phenylalanine Piroxicam Propranolol Ranitidine Terbutaline Valacyclovir Verapamil

Ability to Correctly Classify BCSPermeability for Estimated CLog P andLog P vs. Metabolism as Compared toHuman Jejunal Permeability Measures

93.1% 70.4% 65.5%

27 of 29 19 of 27 19 of 29

Extensive vsPoor Metabolism

Log P CLog P

Values of CLogP, Log P and Measured Human Permeability forMetoprolol and the 11 Drugs Where Predicted Permeabilities or Extent ofMetabolism Did Not Match Measured Permeability Relative to Metoprolol

(Values from Takagi et al., Mol. Pharm. 3:631-643, 2006)

HH1.66L-1.06L-1.22valacyclovir

HH6.65L0.29H1.89piroxicam

HH4.08L0.78L-1.56phenylalanineHH1.34H1.72H1.49metoprolol

HL1.15H4.11losartan

HH6.20L0.34L-1.67L-leucine

HH3.40L0.00L-2.82Levodopa

LL0.05L0.74H1.90furosemide

H H1.57H1.77L0.67enalapril

H H10.00L-2.38L-2.21D-glucose

L H1.56L-0.67L-1.84cephalexin

HH5.60L1.01L0.20antipyrine

MetabolismPermeability

MeasuredHuman

Permeability(x104cm/sec)

PredictedPermeabilityLog P

PredictedPermea-

bilityCLogPDrug

not available

YesYesLowRanitidine

YesYesLow (zero permeability marker)Polyethylene glycol (4000)

YesYesLowPolyethylene glycol (1000)


YesYesLow_-Methyldopa

YesYesLow (Potential IS candidate)Mannitol

YesYesLowHydrochlorthiazide

YesNoLowFurosemide

YesYesLowAtenolol

YesYesLowAmoxicillin

YesYesHigh (Potential ES Candidate)Verapamil

YesNoHighTheophyllineYesYesHighPropranolol

YesYesHighNaproxen

YesYesHigh (Potential IS candidate)Metoprolol

YesYesHighKetoprofen

YesYesHighFluvastatin

YesYesHighCarbamazepine

YesNoHighCaffeine

YesNoHigh (Potential IS candidate)Antipyrine

Predicted byExtent ofMetabolism a

Predicted byCLogP andLog P

Permeability Class20 Model Drugs Suggested by FDAfor Use in Establishing Suitabilityof a Permeability Method

a Using 70% as the cutoff

Since extent of metabolism correctly predicts highvs low intestinal permeability for at least 33 of 35drugs, and may in fact correctly predict all 35

model compounds, Benet and co-workersa proposethe following:

a Benet, Amidon, Barends, Lennerns, Polli, Shah, Stavchansky & Yu.The Use of BDDCS in Classifying the Permeability of Marketed Drugs,

Pharm. Res., submitted August 2007

We recommend that regulatory agencies addthe extent of drug metabolism (i.e., 90%metabolized) as an alternate method for theextent of drug absorption (i.e., 90% absorbed)in defining Class 1 drugs suitable for a waiverof in vivo studies of bioequivalence.

We propose that the following criteria be used todefine 90% metabolized for marketed drugs:

Following a single oral dose to humans,administered at the highest dose strength, massbalance of the Phase 1 oxidative and Phase 2conjugative drug metabolites in the urine and feces,measured either as unlabeled, radioactive labeled ornonradioactive labeled substances, account for 90% of the drug dosed. This is the strictestdefinition for a waiver based on metabolism. For anorally administered drug to be 90% metabolized byPhase 1 oxidative and Phase 2 conjugativeprocesses, it is obvious that the drug must beabsorbed.


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Class 1Marketed Drugs~35%NMEs: 5%



Distribution of Drugs on the Marketvs. Small Molecule NMEs


A major advantage of BDDCS is that drugscan generally be correctly classified without

running expensive and time consumingpermeability studies in humans.

At this time, BDDCS may not be sufficient forthe regulatory agencies, but it gives scientists a

roadmap for predicting drug disposition anddrug-drug interaction characteristics very early

and with little additional expense.

Lets see further predictions

Cellular and animal studies from ourlaboratory over the past seven years

examining transporter-enzyme interplayled us to make 22 predictions concerning

drug absorption and disposition.

The justification for these predictions, aswell as predictions not specificallydiscussed here, may be found in ourJanuary 2005 Pharmaceutical Researchpaper

C-Y. Wu and L.Z. Benet. Pharm. Res. 22:11-23 (2005)


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Class 1Transportereffects minimal ingut and liver

Class 3Absorptivetransporter effectspredominate (but canbe modulated by effluxtransporters)

Class 4Absorptive andefflux transportereffects could beimportant

Oral Dosing Transporter Effects

Class 2Efflux transportereffects predominate ingut, but both uptake &efflux transporterscan affect liver

Class 1highly soluble, high permeability,

extensively metabolized drugs

Transporter effects will be minimalin the intestine and the liver

Even compounds like verapamil thatcan be shown in certain cellularsystems (MDR1-MDCK) to be asubstrate of P-gp will exhibit noclinically significant P-gp effects inthe gut and liver

Papp Values for Verapamilin Caco-2 and MDR1-MDCK Cells

(Sahin, Custodio and Benet, AAPS, November 2007)

80.3 3.789.4 3.510M+0.5M GG918

130.4 3.831.5 1.310 M

54.1 0.562.6 0.910nM+0.5M GG918

127.0 6.19.1 0.310 nMMDR1-MDCK

82.9 2.291.3 1.210M+0.5M GG918

84.5 2.993.3 4.110 M

73.1 2.072.4 4.710nM+0.5M GG918

71.2 3.665.2 2.910 nMCaco-2

B-to-AA-to-B

PERMEABILITY (nm/s)ConcentrationCell Line

Class 1 drugsA major proposition (and probablythe primary advance in knowledge) ofBDDCS is that Class 1 drugs arenot substrates for transporters in

the intestine and liver(but the BBB and the kidney are not

the gut and liver)

YesYesLowRanitidine

YesYesLow (zero permeability marker)Polyethylene glycol (4000)



YesYesLow_-Methyldopa

YesYesLow (Potential IS candidate)Mannitol

YesYesLowHydrochlorthiazide

YesNoLowFurosemide

YesYesLowAtenolol

YesYesLowAmoxicillin

YesYesHigh (Potential ES Candidate)Verapamil

YesNoHighTheophyllineYesYesHighPropranolol

YesYesHighNaproxen

YesYesHigh (Potential IS candidate)Metoprolol

YesYesHighKetoprofen

YesYesHighFluvastatin

YesYesHighCarbamazepine

YesNoHighCaffeine

YesNoHigh (Potential IS candidate)Antipyrine

Predicted byExtent ofMetabolism a

Predicted byCLogP andLog P

Permeability Class20 Model Drugs Suggested by FDAfor Use in Establishing Suitabilityof a Permeability Method

a Using 70% as the cutoff

My reaction to the many studies thatuse midazolam, diazepam and

verapamil as model substrates?

The science is great and thecorrelations are excellent, but somuch of the work is carried out withClass 1 compounds, where we areable to ignore transporter effects.Will the methodology be useful andreliable when we investigate NMEs?

Class 2poorly soluble, highly permeable,

extensively metabolized drugs Efflux transporter effects will be important

in the intestine and the liver

In the intestine efflux transporter enzyme(CYP 3A4 and UGTs) interplay can markedlyaffect oral bioavailability

In the liver the efflux transporter-enzymeinterplay will yield counteractive effects tothat seen in the intestine.

Uptake transporters can be important for theliver but not the intestine.

Current Drug MetabolismCover October 2003 Issue

Predicted AUC Changesfor In Vivo - In Situ Studies

Gut Liver

Inhibit P-gp

Inhibit 3A

Inhibit

P-gp+3A

Rate of Absorption vs Extent ofAbsorption in BCS and BDDCS

It is confusing that the FDA and other regulatoryagencies use a rate parameter, permeability, as a

predictor of the extent of absorption ( 90%absorbed) in BCS. In BDDCS an extent measure

(% metabolized) is used as a predictor of the extentof absorption

This has led some authors to incorrectly believe thatpoorly soluble Class 2 compounds should have

markedly less than 90% absorption. For marketedClass 2 drug products, almost all show high extent

of absorption because of high permeability. Formarketed Class 2 drugs solubility is rate limiting, not

extent limiting.

Class 3highly soluble, low permeability,

poorly metabolized drugs

Uptake transporters will beimportant for intestinal absorptionand liver entry for these poorpermeability drugs

However, once these poorlypermeable drugs get into theenterocyte or the hepatocyte effluxtransporter effects can occur.

It is generally agreed that animals arepoor predictors of drug metabolism in

man, so we asked the opposite question:How good are animals at predicting

not metabolized in man?The Reliability of Animal Models to Predict the Extentof Metabolism for BDDCS Class 3 Drugs in Humans

Yung-Huei Fu and Leslie Z. Benet (PSWC 2007)

For 12 human Class 3 drugs, rats correctly predictclassification for 12 of 12, dogs 10 of 10 and

monkeys 7 of 8

Potential DDIs Predicted by BDDCS

Class 1: Only metabolic in the intestineand liver

Class 2: Metabolic, efflux transporter andefflux transporter-enzyme interplay in theintestine. Metabolic, uptake transporter,efflux transporter and transporter-enzymeinterplay in the liver.

Class 3 and 4: Uptake transporter, effluxtransporter and uptake-efflux transporterinterplay


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Class 2 Fextent Tpeak




Food Effects (High Fat Meals)Fleisher et al., Clin Pharmacokinet.36(3):233-254, 1999

We hypothesize that high fatmeals inhibit transporters

Preliminary results suggestthat the inhibitors are themonoglycerides found inhigh fat meals

(Custodio and Benet, presented at AAPS,November 2006)

High fat meals will have nosignificant effect on Fextent for Class1 compounds since completeabsorption may be expected for highsolubility-high permeabilitycompounds. However, high fatmeals may delay stomach emptyingand therefore cause an increase inpeak time.

High fat meals will increase Fextentfor Class 2 compounds due toinhibition of efflux transporters in theintestine and additional solubilizationof drug in the intestinal lumen. Peaktime can change as a result of anumber of interactive effects, e.g.,slowing stomach emptying versusincreasing absorption rate via effluxtransporter inhibition.

High fat meals will decreaseFextent for Class 3 compounds dueto inhibition of uptake transportersin the intestine.

Peak time would be expected toalways increase due to thecombination of slowing absorptionand stomach emptying.

Conclusions Understanding transporter-enzyme interactions in

terms of the permeability and solubility of drugcompounds offers the potential for predicting:

a. Major routes of elimination

b. Transporter effects of in the gut and liver

c. Food (High Fat Meal) effects

d. Expansion of the regulatory requirement for anin vivo bioequivalence waiver

e. Enzyme transporter interplay

f. Drug-drug interaction potential and itsrelationship to enzyme-transporter interplay

Collaborators & Acknowledgements Carolyn Cummins, PhD Joseph M. Custodio, BS Margarida Estudante, BS Lynda Frassetto, MD Yong Huang, PhD Justine Lam, PhD Yvonne Lau, PhD Hideaki Okochi, PhD Selma Sahin, PhD Chi-Yuan Wu, PhDFunding NIH grants GM 61390, GM 75900, HD 40543 and

an unrestricted grant from Amgen Inc. [email protected]

bcs and bddcs

Documents

quinidine s

amitryptyline s

azithromycin s

carbamazepine s

ator vastatin s

high permeability criteria

bcs canserve

drug substance