Commentary
G.L.Amidon,H.Lennernas,V.P.Shah,and J.R.Crison.A Theoretical Basis for a Biopharmaceutic Drug Classification:The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability ,Pharm Res 12,413–420,1995—Backstory of BCS
Vinod P.Shah 1and Gordon L.Amidon 2,3
Received 25March 2014;accepted 12May 2014;published online 25June 2014
恐怖蜡像馆2Abstract.The Biopharmaceutics Classi fication System (BCS)has become widely accepted today in the academic,industrial,and regulatory world.While the initial application of the BCS was to regulatory science bioequivalence (BE)issues and related implications,it has come to be utilized widely by the pharmaceutical industry in drug discovery and development as well.This brief manuscript will relate the story of the BCS development.While much of the ground work for the BCS goes back to the pharmacokinetic and drug absorption rearch by Gordon Amidon (GLA)in the 1970s and 1980s,the realization of the need for a classi fication or categorization of drug and drug products for tting dissolution standards became apparent to GLA during his 1990–1991sabbatical year at the FDA.Initiated at the invitation of the then CEDR director,Dr.Carl Peck,to become a visiting
scientist at the FDA,the goal was to promote regulatory rearch at the FDA,in my ca,in biopharmaceutics,and to develop a science-bad system to simplify regulatory requirements.KEY WORDS:absorption;biopharmaceutics;dissolution standards;intestinal permeability;solubility.
INTRODUCTION
The Biopharmaceutics Classi fication System (BCS)has become widely accepted today in the academic,industrial,and regulatory world.While the initial application of the BCS was to regulatory science bioequivalence (BE)issues and related implica-tions,it has come to be utilized widely by the pharmaceutical industry in drug discovery and development as well.This brief manuscript will relate the story of the BCS development.While much of the ground work for the BCS goes back to the pharmacokinetic and drug absorption rearch by Gordon Amidon (GLA)in the 1970s and 1980s,the realization of the need for a classi fication or categorization of drug and drug products for tting dissolution standards became apparent to GLA during his 1990–1991sabbatical year at the FDA.Initiated at the invitation of the then CEDR director,Dr.Carl Peck,to become a visiting scientist at the FDA,the goal was to promote regulatory rearch at the FDA,in biopharmaceutics,and to develop a science-bad system to simplify regulatory requirements.
GLA began working with Drs.Vinod Shah and Jerome Skelly in the FDA Division of Biopharmaceutics,in 1990,on the problems of and regulatory standards for drug product dissolu-tion.In reviewing drug product dissolution standards,it became
clear that some drug products were simple while other drug products were complex,suggesting that some type of categori-zation or classi fication would be uful for tting regulatory standards.That is,simple standards for simple drug products and complex standards for complex drug products.Initially,it was not obvious where to start with such a classi fication,though the need and potential utility was clear.A clear starting point would require a sound,well-established scienti fic principle as a starting point for classi fication and it would be critical that the principle be well accepted by the scienti fic community.Where to start and how to build such a classi fication occupied much of the thinking over the 1990–1992time period.
A deeper question was the u of dissolution testing in the regulation of oral drug products.Dissolution testing has been extensively developed and ud as a critical quality control (QC)speci fication for oral drug products.The u of dissolution as a component of the bioequivalence (BE)standard,though clearly recognized as important,was less well developed and less discusd by the scienti fic community.
By 1990,GLA had developed methods for predicting absorption in humans utilizing animal intestinal jejunal perme-abilities (1)for soluble drugs (2),and parated the absorption (fraction absorbed,F abs )and metabolism components of systemic availability (F sys )and was extending the absorption prediction approaches to insoluble drugs (3).The absorption prediction methods clearly established the intestinal membrane permeabil-ity (P eff )as a key variable in human absorption prediction (2,4,5).
As is often the ca in science,parallel developments play a catalyzing role in advancing science;in this ca,
1Pharmaceutical Consultant,North Potomac,Maryland 20878,USA.2
College of Pharmacy,University of Michigan,Ann Arbor,Michigan 48109,USA.3
To whom correspondence should be addresd.(e-mail:glamidon@med.umich.edu)
The AAPS Journal,Vol.16,No.5,September 2014(#2014)DOI:10.1208/s12248-014-9620-9
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1550-7416/14/0500-0894/0#2014American Association of Pharmaceutical Scientists
Dr.Hans Lennernas,then a graduate student of Dr. Lennart Paalzow at the University of Uppsala,adapted and developed an intubation technique,the Loc-I-Gut®, for determining intestinal permeability in humans(6–8), utilizing the methods we had developed for animals(1,4). The availability of human data,in this ca,intestinal permeabilities,was crucial,in my mind,for making any type of regulatory advance.Further,the availability of a human databa would be“gold”standard for absorption prediction(2).
The BCS approach to classifying drug and drug products crystallized during the1991–1992time period. Methods were developed for predicting fraction absorbed (F abs)for soluble drugs and work was in progress to predict absorption of insoluble drugs(2,3,9).It became clear that Fick’sfirst law applied to a membrane,where drug partitioned into a membrane,and where permeabil-ity replaced the diffusivity of Fick’sfirst law was the scientific conceptual starting point for a classification.The intestinal membrane permeability was a boundary condi-tion on the differential equations for predicting absorption (1),while the drug solubility was the upper limit to drug concentration at the membrane aqueous interface.Thus, the equation or,actually,the boundary condition to the above noted transport equations
J max¼1=A
农业数字化ðÞdM=dt¼P effÂC sðEq:1:Þbecame the scientific basis for the BCS approach.In Eq.1, theflux(J)is the mass(M)per unit area(A)absorbed in to the membrane per unit time(t)and is determined by the product of the local membrane permeability(P eff)and the concentration(C)at the membrane luminalfluid interface, with the maximum concentration being the solubility(C s). This suggested a strong scientific basis for the permeability–solubility classification system.While the complexity of the intestinal membrane permeability(P eff)and the solubility (C s)in the gastrointestinal track was well recognized at the time of the original publication and the draft FDA guidance, the permeability and solubility would be a pivotal starting point for BCS classification.
Thus,bad on mass transport analysis of the gastroin-testinal tract,the BCS classification system was propod to the FDA.The critical need for development and particularly, for the regulatory u of the BCS was human , human permeabilities with which to support a regulatory standard or guidance.
Thus,Hans Lennernas and GLA convinced the FDA and the Swedish Medicine Products Agency(MPA)to fund a study to determine human jejunal permeabilities with the former’s newly developed“Loc-I-Gut”technique(6,8)and evaluate the basis for a Biopharmaceutics Classification System(BCS).Dr.Larry Lesko of the FDA managed the permeability studies that were conducted at U
ppsala University and the University of Michigan to determine drug permeabilities of three lected drugs in each BCS class.
The BCS approach continued to evolve over veral years under the FDA rearch contract with Gordon and Hans as PI’s and Vinod as the project officer.The goal of this rearch was to develop a sound science-bad system to improve and potentially simplify the FDA BE regulatory standards.Clearly,a standard would have to be t on the product dissolution that would account for various excipient and formulation factors in a product.
Following the publication of the scientific paper in1995 (10),the FDA continued internal discussion with additional scientists and public workshops.At this point,the FDA added a new scientist,Dr.Ajaz Hussain,to the BCS project, who continued to manage the FDA’s internal development of the regulatory guidance.GLA returned to the FDA for veral months in the spring of1995to work with Dr.Hussain and contributed to developing the BCS draft guidance.The BCS draft guidance was then reviewed internally at the FDA and in a ries of expert meetings at the FDA.During this time period,1995–1999,GLA,in addition to participating in the FDA conferences,made numerous public scientific prentations at public workshops,worldwide,sponsored by AAPS,FIP,and other organizations,fully testing out the scientific acceptance of the BCS approach.It was important that B
CS have a sound,well-accepted scientific basis and support so that FDA would feel comfortable in moving away from an in vivo standard to an in vitro standard for ensuring BE.The BCS approach to BE regulation reprented a major paradigm shift in BE regulatory standards for the FDA.The FDA had to be sure the BCS was sound and could withstand broad scientific evaluation and establish a solid scientific connsus.
The working draft of the BCS guidance was published in 1999with a request for comments as is the norm.Surprisingly, only a few comments were made to the FDA on the draft guidance and thefinal guidance was published in August 2000,with esntially no changes(11).This was no doubt due to the extensive public prentations and discussions of the BCS approach prior to the relea of the draft BCS guidance.
The well-accepted BE criteria,AUC and Cmax,are relatively empirical.They are not particularly mechanistic from the biopharmaceutic point of view.The drug dissolution standards,on the other hand,can be t on a mechanistic basis.If two drug products have the same in vivo dissolution profile under all luminal conditions,they will have the same rate and extent of absorption,and will be bioequivalent(10). The BCS places drugs in class depending on the rate determining step controlling drug absorption.If the rate determining step is gastric emptying,which is the ca for high-
permeability drugs in solutions and in very rapidly dissolving immediate relea(IR)dosage forms,then plasma levels do not provide any information relative to the biopharmaceutic differences in the two products tested(same API).This class of high solubility–high permeability–rapidly dissolving drugs is thefirst class in which the FDA allows in vitro standards to be ud to ensure BE.For a high-permeability drug,which is well absorbed,it is not important to regulate on the basis of AUC since the drugs are completely absorbed(obviously a dissolution standard has to be met).Thus,the BCS approach simplified the BE regulatory requirements and initiated a scientific mechanistic basis for approaching BE.
BCS GUIDANCE
The BCS is a scientific framework for classifying drug substances bad on their aqueous solubility and intestinal permeability(11).When combined with the dissolution of the
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drug product,BCS takes into account the three major factors that govern the rate and extent of absor
ption from immediate relea solid oral dosage forms,namely, dissolution,solubility,and intestinal permeability(absorp-tion).Using the principles of solubility and permeability, the drug substances can be classified into four class: class1—highly soluble and highly permeable;class 2—poorly soluble but highly permeable;class3—highly soluble but poorly permeable;and class4—poorly soluble and poorly permeable.
面试自我介绍范文For regulatory u,boundaries had to be t on permeability,solubility,and dissolution.The starting point was the8oz(240ml)of water taken with a typical in vivo BE study.This volume,plus the variable residual volume of liquid in the stomach of about25–50ml,lead to lecting a conrvative volume of250ml for the solubility of the highest do strength typically ud in in vivo BE studies.Thus a high-solubility drug is bad on the minimum thermodynamic equilibrium solubility over the pH range of1–7.4.A suitable number of data points were suggested in the guidance including consideration of drugs with p K a’s in the3–5range.
A highly soluble drug is defined as a drug where the highest marketed do(highest do strength)is soluble in 250ml of aqueous media in over the entire gastrointestinal pH range(1.2–7.4),a conrvative definition.A dosage form is usually marketed in veral strengths and it was decided to u the highest strength that is marketed for the high-soluble drug determination.This is also the cas
e with the BE studies, where the highest strength generally has to be ud.Thus,a high-soluble drug is one that would be soluble over the entire pH range from the stomach through the upper small intestine.
“Highly permeable”means the extent of absorption (including intestinal and liverfirst pass metabolism)is greater than90%of the do administered.Absorption is,thus,taken to be the transport of the drug into thefirst cell,tissue,or interstitialfluid through the tight junctions between the intestinal epithelial cells.This definition was bad on the human jejunal permeability databa established bad on permeability studies performed at the University of Uppsala and Michigan.The90%fraction absorbed defines the lower limit for a highly permeable drug.Bad on the FDA and Swedish MPA data ba and additional intestinal permeabil-ity results,metoprolol(12–16)was lected as the reference drug.Recently,there have been veral workshops and publications suggesting the relaxation of the absorption requirements from90%to85%and at the same time,to consider the aqueous media pH range to be1.2–6.8rather than1.2–7.4.The initial permeability and dissolution limits were recognized as very conrvative at the time of the draft guidance,but it was felt that more data and experience was needed to relax the standards.Permeability was determined in human intestinal jejunum.The permeability of metoprolol was designated as a cutoff point.Active pharmaceu
tical ingredients(APIs)having higher permeability were designat-ed as highly permeable and APIs with lower permeability were classified as low permeable.
Dissolution test for the products is to be carried out under mild conditions,USP basket method at100rpm or paddle method at50rpm in pH1.2,4.5,and6.8aqueous buffer solutions,covering the stomach,duodenum and upper small intestine.The pH of6.8was chon to be consistent with the current USP requirement.A pH of6.5,the pH at which jejunal permeabilities(P eff)were determined and reprentative of the average upper jejunal pH(6,8),was considered but the difference was considered small and of no conquence except potentially for very lect drugs with p K a in the approximately pH~6range.The drug product should dissolve at least85%in15min.,or30min or less and should meet dissolution profile similarity criteria using f2for the30-min ca,when compared with the reference product for biowaiver.According to the FDA Guidance,this was thefirst guidance having“waiver”in the title;only class1drug products are eligible for FDA biowaivers.For biowaivers,the dissolution of the test dosage form should be compared with the dissolution of the reference-listed drug(RLD)product.
The biowaiver guidance bad on the biopharmaceutics classification system(BCS)suggests that documentation of bioequivalence via dissolution studies may be appropriate for BCS class1orally ad
ministered immediate relea drug products.This waiver criterion is not applicable to narrow therapeutic index(NTI)drugs.This requirement was includ-ed bad on safety considerations,though scientifically,it was less clear that it should be a requirement at the time of the draft guidance.A NTI drug product with a BCS class1drug that dissolved rapidly would again be rate limited by gastric emptying.However,the potential that excipients,tablet or capsule,or even shape,could alter gastric emptying could not be ruled out at the time of the draft BCS guidance and the conrvative position of excluding NTI drugs for BCS-bad biowaivers was included in the guidance.
Moving to an in vitro measure to ensure bioequivalence is a major paradigm shift,an extremely important step towards approval of drug products.Maintaining drug product safety,efficacy,and quality to the best of our scientific ability is esntial.The dissolution testing for in vivo bioequivalence (dissolution profile comparison in multimedia reprenting the entire GI tract)is more elaborate than a typical single point quality control(QC)test.Thus BCS was established on sound scientific principles and has led to a major paradigm change in the bioequivalence(BE)standards for insuring drug product therapeutic equivalence.
WHO GUIDANCE
The Biowaiver Guidance issued by the FDA provided biowaivers for BCS class1drug ,tho which are highly soluble and highly permeable.This guidance has been viewed by veral scientists to be highly conrvative.A group of ten international scientists which included both of us (VPS and GLA),met under the auspices of WHO for3days to consider and discuss the extension of the BCS principles to provide biowaivers for other class of drug products.It was concluded that drugs belonging to BCS ,highly soluble but with low permeability and very rapidly dissolving can also be eligible for biowaivers(17).Taking the points into consideration,about60%–70%of the drug products were identified in the WHO Esntial Medicine List as being eligible for BCS-bad biowaivers and can be approved for marketing bad on dissolution criteria.This would reduce regulatory burden and make the drug products more affordable while insuring their quality.The WHO,while not
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a regulatory body,has substantial influence on the tting of drug product regulatory standards in numerous countries around the world.It was felt that extending BCS would assist countries worldwide in insuring drug product therapeutic equivalence for a wider lection of esntial medicines.
After the initial concept of BCS was propod,it took almost5years before the BCS paper was published in1995, and it took an additional5years before thefinal FDA guidance was published in August2000,and an additional 6years before the WHO guidelines using BCS for biowaivers was published.This additional length of time was primarily utilized in holding national and international conferences and workshops discussing BCS,and making sure that we were moving forward with a sound,widely accepted,science-bad public policy on BE product standards.This illustrates that slow and necessary steps are needed to generate a scientific connsus and,most importantly,to incorporate scientific advance into public policy with its numerous additional issues.
BCS AND BDDCS
Analyzing a BCS classification of marketed drugs(18)in the four groups of the biopharmaceutics classification system, Wu and Benet made a very striking obrvation:drugs in class1and2were highly metabolized whereas drugs in class3and4were eliminated by liver or kidney as unchanged drug(19).In addition to this,Wu and Benet made many additional obrvations and predictions bad on the BCS classification,and they termed this as “Biopharmaceutics Drug Disposition Classification System (BDDCS).”
怎么挑牛油果
While the BDDCS classification is bad on a fraction metabolized and the BCS bad on a fraction absorbed,the BCS and BDDCS are quite cloly related.The two classifications are approximately90%equivalent with the exceptions being,for example,drugs that are absorbed by an intestinal carrier-mediated transport ,polar and high permeability.BCS and BDDCS do have significant different purpos.The BCS is focud on oral intestinal absorption and is ud to provide biowaivers for in vivo BE studies,bad on solubility,permeability(absorption),and dissolution.On the other hand,the purpo of BDDCS is the prediction of the major route of drug elimination(drug disposition),transporter effect on drug absorption,trans-porters,and enzyme interplay and potential drug–drug interaction in the intestine and liver.The BCS and BDDCS together point to an exciting new era of molecular absorption, distribution,metabolism,and excretion(ADME). LOOKING INTO THE FUTURE
As experience is gained by using BCS,and its ufulness is realized worldwide,further refinements of the regulatory requirements is very likely,particularly with regard to the most predictive in vivo dissolution methodology.This meth-odology will better reflect the in vivo dissolution conditions than the current QC dissolution requirement.This in vivo predictive dissolution methodology is a scientific area in need of significant future rearch studies to best define and t dissolution methodology sta
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ndards.There is also a suggestion of further subdividing BCS class2and4drugs into weak acids,weak bas,and neutral compounds and to further develop dissolution requirements for biowaivers(20)bad on this subclassification.
This subdivision,bad on obvious physical chemical principles,may lead to the tting of dissolution methodolo-gies bad on drug class and sub class,and rve as a basis for further extension of the biowaiver approach to ensuring drug product therapeutic interchangeability.
The regulatory acceptance and even the harmoniza-tion process among all regulatory authorities will no doubt take considerable time.However,the process of establish-ing a scientific connsus is the esntial starting point for public policy change.The BCS approach and the associ-ated FDA guidance has t a new direction that will no doubt continue to be developed and provide a sound, mechanistic,scientific basis for tting pharmaceutical drug product performance standards that will be applicable worldwide.
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