Date post: | 19-Oct-2015 |
Category: |
Documents |
Upload: | siri-kalyan |
View: | 50 times |
Download: | 1 times |
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
Hig
h
Per
mea
bili
tyL
ow
P
erm
eab
ility
1 2
3 4
Amidon et al., Pharm Res 12: 413-420, 1995
CarbamazepineCyclosporineDigoxinKetoconazoleTacrolimus
AcetaminophenPropranololMetoprololValproic acid
CimetidineRanitidine
ChlorothiazideFurosemideMethotrexate
Biopharmaceutical Classification
High Solubility Low Solubility
Hig
h
Per
mea
bili
tyL
ow
P
erm
eab
ility
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
High Solubility Low Solubility
Hig
h P
erm
eab
ility
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)
High Solubility Low Solubility L
ow
Per
mea
bili
ty
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)
High Solubility Low Solubility
Hig
h
Per
mea
bili
tyL
ow
P
erm
eab
ility
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
Ext
ensi
veM
etab
olis
mP
oo
r M
etab
olis
mClass 2Low SolubilityExtensive Metabolism
Class 1High SolubilityExtensive Metabolism(Rapid Dissolution and 70% Metabolism for Biowaiver )
Class 3High SolubilityPoor Metabolism
Class 4Low SolubilityPoor Metabolism
High Solubility Low Solubility
Hig
h P
erm
eab
ility
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)
YesYesLowPolyethylene glycol (400)
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.
High Solubility Low Solubility
Hig
h
Per
mea
bili
tyL
ow
P
erm
eab
ility
Class 1Marketed Drugs~35%NMEs: 5%
Class 3Marketed Drugs~25%NMEs: 5%
Class 4Marketed Drugs~10%NMEs: 20%
Distribution of Drugs on the Marketvs. Small Molecule NMEs
Class 2Marketed Drugs~30%NMEs: 70%
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)
High Solubility Low Solubility
Hig
h
Per
mea
bili
ty/
Met
abo
lism
Lo
w
Per
mea
bili
ty/
Met
abo
lism
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)
YesYesLowPolyethylene glycol (1000)
YesYesLowPolyethylene glycol (400)
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
High Solubility Low Solubility
Hig
h
Per
mea
bili
tyL
ow
P
erm
eab
ility
Class 2 Fextent Tpeak
Class 1 Fextent Tpeak
Class 3 Fextent Tpeak
Class 4 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]