1

Presented By
Peeyush Kumar Sharma
M.Pharm(Pharmaceutics)
BIOAJAILABILI1Y AAD BIOAJAILABILI1Y AAD
BIOEQUIJALEACE BIOEQUIJALEACE
8ICAVAILA8ILI1
8loavallablllLy ls a pharmacoklneLlc Lerm LhaL
descrlbes Lhe raLe and exLenL Lo whlch Lhe
acLlve drug lngredlenL ls absorbed from a drug
producL and becomes avallable aL Lhe slLe of
drug acLlon
1hus bloavallablllLy ls concerned wlLh how
qulckly and how much of a drug appears ln
Lhe blood afLer a speclflc dose ls admlnlsLered
1he bloavallablllLy of a drug producL ofLen
deLermlnes Lhe LherapeuLlc efflcacy of LhaL
producL slnce lL affecLs Lhe onseL lnLenslLy
and duraLlon of LherapeuLlc response of Lhe
drug
A8SCLu1L 8lCAvAlLA8lLl1?
AbsoluLe bloavallablllLy l ls Lhe fracLlon of an
admlnlsLered dose whlch acLually reaches Lhe sysLemlc
clrculaLlon and ranges from l 0 (no drug absorpLlon) Lo l
1 (compleLe drug absorpLlon)
l ls deLermlned by comparlng Lhe respecLlve AuCs of Lhe LesL
producL and Lhe same dose of drug admlnlsLered
lnLravenously 1he lnLravenous rouLe ls Lhe reference sLandard
slnce Lhe dose ls by deflnlLloncompleLely avallable
l Aucev/Auclv
LLA1lvL 8lCAvAlLA8lLl1?
elaLlve or ComparaLlve" bloavallablllLy refers Lo Lhe
avallablllLy of a drug producL as compared Lo anoLher dosage
form or producL of Lhe same drug glven ln Lhe same dose
1hese measuremenLs deLermlne Lhe effecLs of formulaLlon
dlfferences on drug absorpLlon 1he relaLlve bloavallablllLy of
producL A compared Lo producL 8 boLh producLs conLalnlng
Lhe same dose of Lhe same drug ls obLalned by comparlng
Lhelr respecLlve AuCs
elotlve8loovollobllty Auc
A
/Auc
8
\AMllelotlve 8loovolloblllty of oo otol Josoqe fotm wtt
oo otol stooJotJ(otol solotloo)
C8!LC1lvLS Cl 8lCAvAlLA8lLl1?
rlmary sLage of developmenL for sulLable dosage form for a new
drug enLlLy
ueLermlnaLlon of lnfluence of exclplenLs paLlenL relaLed facLors and
posslble lnLeracLlon wlLh oLher drugs on Lhe efflclency of absorpLlon
lor a approved drugs Lo develop a new dosage form or Lo lmprove
an exlsLlng dosage form
1o flnd ouL Lhe lnfluence of physlcochemlcal properLles of drug and
dosage form on blologlcal performance of Lhe drug
useful ln deLermlnlng Lhe safeLy and efflcacy of Lhe drug producL
,L1PCuS Cl uL1L,lnA1lCn Cl
8lCAvAlLA8lLl1?
|asma drug concentrat|on
1lme for peak plasma (blood) concenLraLlon (t
mox
)
eak plasma drug concenLraLlon (c
mox
)
Area under Lhe plasma drug concenLraLlonLlme curve (AuC)
Dr|nary drug excret|on
CumulaLlve amounL of drug excreLed ln Lhe urlne (o)
aLe of drug excreLlon ln Lhe urlne (Jo/Jt)
1lme for maxlmum urlnary excreLlon (t)
Acute pharmacodynam|c effect
,axlmum pharmacodynamlc effecL (mox)
1lme for maxlmum pharmacodynamlc effecL
lnvitro studies
urug dlssoluLlon
LAS,A uuC CCnCLn1A1lCn1l,L
S1uulLS
lasma urug ConcenLraLlon ,easuremenL of drug
concenLraLlons ln blood plasma or serum afLer drug
admlnlsLraLlon ls Lhe mosL dlrecL and ob[ecLlve way Lo
deLermlne sysLemlc drug bloavallablllLy
1he key parameLers Lo noLe are
AD 1he area under the p|asma concentrat|ont|me curve
1he AD |s proport|ona| to the
LoLal amounL of drug reachlng Lhe sysLemlc clrculaLlon and Lhus
characLerlzes Lhe exLenL of
absorpLlon
max 1he max|mum drug concentrat|on 1he max|mum
concentrat|on of drug |n the p|asma ls a funcLlon of boLh Lhe
raLe and exLenL of absorpLlon max w||| |ncrease w|th an
|ncrease |n Lhe dose as well as wlLh an lncrease ln Lhe
absorpLlon raLe
3 1max 1he t|me at wh|ch the max occurs 1he 1max ref|ects
the rate of drug absorpt|on and decreases as Lhe absorpLlon
raLe lncreases
Area under Lhe ConcenLraLlon 1lme
Curve (AuC)
A quanLlLaLlve measure for
exposure from doslng Llme Lo
Llme 'L'
AuC
(L)
and AuC
(lnf)
ueLermlned by Lrapezoldal
meLhod
AuC
(lnf)
AuC
(L)
+ C
L
/k
unlLs Conc*L (mg/L * h)
roporLlonal Lo uose (llnear
k)
Accuracy of Lhe esLlmaLe
depends on frequency of
sampllng
Dr|nary Lxcret|on Data
An alLernaLlve bloavallablllLy sLudy measures Lhe
cumulaLlve amounL of unchanged
drug excreLed ln Lhe urlne 1hese sLudles lnvolve
collecLlon of urlne samples and
Lhe deLermlnaLlon of Lhe LoLal quanLlLy of drug
excreLed ln Lhe urlne as a funcLlon of Llme 1hese
sLudles are based on Lhe premlse LhaL urlnary
excreLlon of Lhe
unchanged drug ls dlrecLly proporLlonal Lo Lhe
plasma concenLraLlon of LoLal drug
deLermlnaLlon of bloavallablllLy uslng urlnary
excreLlon daLa should be conducLed
only lf aL leasL 20 of a dose ls excreLed unchanged ln
Lhe urlne afLer an lv dose
Lhe fracLlon of drug enLerlng Lhe bloodsLream and
belng excreLed lnLacL by Lhe kldneys musL
remaln consLanL
collecLlon of Lhe urlne has Lo conLlnue unLll all Lhe
drug has been compleLely excreLed (flve Llmes
Lhe halfllfe
|ng|edose versus
Mu|t|p|eDose
Jhen a drug ls admlnlsLered repeaLedly aL flxed
lnLervals wlLh Lhe doslng frequency less Lhan flve half
llves drug wlll accumulaLe ln Lhe body and evenLually
reach a plaLeau or a sLeadysLaLe
AL sLeadysLaLe Lhe amounL of drug ellmlnaLed from
Lhe body durlng one doslng lnLerval ls equal Lo Lhe
avallable dose (raLe ln raLe ouL) Lherefore Lhe area
under Lhe curve durlng a doslng lnLerval aL sLeadysLaLe
ls equal Lo Lhe LoLal area under Lhe curve obLalned
when a slngle dose ls admlnlsLered 1hls AuC can
Lherefore be used Lo assess Lhe exLenL of absorpLlon of
Lhe drug as well as lLs absoluLe and relaLlve
bloavallablllLy
AdvanLages
- LllmlnaLes Lhe need Lo exLrapolaLe Lhe plasma concenLraLlon
proflles Lo obLaln Lhe LoLal AuC
afLer a slngle dose
- LllmlnaLes Lhe need for a long washouL perlod beLween doses
- ,ore closely reflecLs Lhe acLual cllnlcal use of Lhe drug
- Allows blood levels Lo be measured aL Lhe same concenLraLlons
encounLered LherapeuLlcally
- 8ecause blood levels Lend Lo be hlgher Lhan ln Lhe slngledose
meLhod quanLlLaLlve deLermlnaLlon
ls easler and more rellable
- SaLurable pharmacoklneLlcs lf presenL can be more readlly
deLecLed aL sLeadysLaLe
LlmlLaLlons
- equlres more Llme Lo compleLe
- ,ore dlfflculL and cosLly Lo conducL
(requlrlng prolonged monlLorlng of sub[ecLs
- CreaLer problems wlLh compllance conLrol
- CreaLer exposure of sub[ecLs Lo Lhe LesL
drug lncreaslng Lhe poLenLlal for adverse
reacLlons
1DD DLIGN
Lhe sLudy ls conducLed ln a group of healLhy male sub[ecLs
who are of normal helghL and welghL and range ln age
from 18 Lo 33 years
reasons for uslng healLhy volunLeers raLher Lhan paLlenLs
ln bloavallablllLy sLudles lL ls assumed LhaL Lhere are no
physlologlc changes ln Lhe sub[ecLs durlng Lhe course of Lhe
sLudy lf acLual paLlenLs were used Lhls would noL be a valld
assumpLlon due Lo posslble changes ln Lhe dlsease sLaLe
drugdrug lnLeracLlon
dleL and
fluld volume lnLake are more dlfflculL Lo conLrol
CLher lmporLanL conslderaLlons ln Lhe
meLhodology of a bloavallablllLy sLudy are sample
slze perlod of Lrlal and sampllng
lor sLaLlsLlcal purposes Lwelve sub[ecLs are
consldered Lo be a mlnlmum sample slze
1he bloavallablllLy LesLlng perlod should be of a
sufflclenL lengLh of Llme Lo ensure LhaL drug
absorpLlon has been compleLed 1hls lengLh of
Llme ls aL leasL Lhree Llmes Lhe halfllfe of Lhe
drug generally a perlod of four Lo flve Llmes Lhe
halfllfe ls used
A1Ck INLDLNING
8ICAVAILA8ILI1
1 hys|cochem|ca| propert|es of the drug
arLlcle slze
CrysLalllne sLrucLure
uegree of hydraLlon of crysLal
SalL or esLer form
ormu|at|on and manufactur|ng var|ab|es
AmounL of dlslnLegranL
AmounL of lubrlcanL
Speclal coaLlngs
naLure of dlluenL
Compresslon force
3 hys|o|og|c factors
varlaLlons ln absorpLlon power along Cl LracL
varlaLlons ln pP of Cl flulds
CasLrlc empLylng raLe
lnLesLlnal moLlllLy
erfuslon of Cl LracL
resysLemlc and flrsLpass meLabollsm
Age sex welghL
ulsease sLaLes
Interact|ons w|th other substances
lood
lluld volume
CLher drugs
,L1PCuS Cl LnPAnCL,Ln1 Cl
8lCAvAlLA8lLl1?
1he Lhree ma[or approaches ln overcomlng Lhe bloavallablllLy
problem are
1he harmaceuLlcal approach whlch lnvolves modlflcaLlon of
formulaLlon manufacLurlng process or Lhe physlcochemlcal
properLles of Lhe drug wlLhouL changlng Lhe chemlcal sLrucLure
1he chemlcal approach ln whlch Lhe pharmacoklneLlcs of Lhe drug ls
alLered by modlfylng lLs chemlcal sLrucLure 1hls approach lncludes
salL formaLlon or lncorporaLlng polar or lonlzable groups ln Lhe maln
drug sLrucLure resulLlng ln Lhe formaLlon of prodrug
1he 8lologlc approach whereby Lhe rouLe of drug admlnlsLraLlon
may be changed such as changlng from oral Lo parenLral rouLe
1PL PA,ACLu1lCAL ACACP
1he harmaceuLlcal Approach can be
classlfled on Lhe basls of Lhe physlcal properLy
lL alms aL modlfylng
1 LnhancemenL of urug SolublllLy
2 LnhancemenL of drug ermeablllLy
3 LnhancemenL of drug SLablllLy
LnhancemenL of CasLrolnLesLlnal eLenLlon
,L1PCuS Cl LnPAnCL,Ln1 Cl
uuC SCLu8lLl1?
o||d D|spers|ons
oprec|p|tat|on method
3 Nanos|z|ng
4 M|cron|zat|on
S Lyoph|||zat|on
6 Dse of urfactants
7 Dse of a|t forms
8 A|terat|on of pn of the Drug M|croenv|ronment
9 Dse of more so|ub|e metastab|e po|ymorphs
o|uteso|vent comp|exat|on
o|vent depos|t|on
e|ect|ve adsorpt|on on |nso|ub|e carr|ers
3 o||d so|ut|ons
4 Lutet|c M|xtures
S Mo|ecu|ar encapsu|at|on and cyc|odextr|ns
,L1PCuS Cl LnPAnCL,Ln1 Cl
uuC L,LA8lLl1?
1 Llpld SoluLlons and Suspenslons
2 Coarse
Lmulslons,lcroemulslonsSLuuSS,LuuS
3 Solld Llpld nanoparLlcles
nLC
3 LuC nanoparLlcles
6 lon palrlng
7 eneLraLlon Lnhancers
,L1PCuS Cl LnPAnCL,Ln1 Cl
uuC S1A8lLl1?
1 LnLerlc CoaLlng
2 ComplexaLlon
3 use of ,eLabollsm lnhlblLor
urug dlssoluLlon raLe and relaLed Lheorles urug dlssoluLlon raLe and relaLed Lheorles
uef lL ls deflned as Lhe amounL of solld subsLance LhaL goes lnLo soluLlon
per unlL Llme under sLandard condlLlons of LemperaLure pP and solvenL
composlLlon and consLanL solld surface area
lL ls a dynamlc process and consldered Lo lnvolve mass Lransfer
ulssoluLlon 1esLs Slnce a drug musL go lnLo soluLlon before lL can be
absorbed and slnce Lhe raLe aL whlch a drug dlssolves from a dosage form
ofLen deLermlnes lLs raLe and/or exLenL of absorpLlon aLLenLlon has been
dlrecLed aL Lhe dlssoluLlon raLe lL ls currenLly consldered Lo be Lhe mosL
senslLlve lnvlLro parameLer mosL llkely Lo correlaLe wlLh 8loavallablllLy
Some of dlssoluLlon Lheorles sLaLed below
ulffuslon layer model/noyesJhlLney Lheory
uanckwerL's model/Surface renewal Lheory
lnLerfaclal barrler model/LlmlLed solvaLlon Lheory
ulffuslon layer model
Accordlng Lo Lhls Lheory dlffuslon
conslsLs of 2 consecuLlve sLeps
*lormaLlon of a sLagnanL fllm over
Lhe drug surface
*ulffuslon of soluble soluLe from Lhe
sLagnanL fllm
elaLed equaLlon glven by noyes
JhlLney was
k(CsC)
/ /
/9 /9
uanckwerL's model
lnsLead of sLagnanL fllm he suggesLed LhaL Lurbulence ln Lhe dlssoluLlon
medlum exlsLs aL Lhe solld llquld lnLerface uue Lo whlch Lhese
macroscoplc eddles LhaL formed absorb Lhe soluLe by dlffuslon and carry
Lo Lhe bulk Lxpressed equaLlon ls
A(CsC)v(u)
lnLerfaclal 8arrler model
8ased on solvaLlon mechanlsm raLher Lhan dlffuslon
ulffuslvlLy may noL be lndependenL of saLuraLlon concenLraLlon
lL ls glven by followlng equaLlon
Ckl(CsC)
/ /
' '
/9 /9
/2 /2
/9 /9
D|sso|ut|on 1ests
Slnce a drug musL go lnLo soluLlon before lL
can be absorbed and slnce Lhe raLe aL whlch a
drug dlssolves from a dosage form ofLen
deLermlnes lLs raLe and/or exLenL of
absorpLlon aLLenLlon has been dlrecLed aL Lhe
dlssoluLlon raLe lL ls currenLlyconsldered Lo be
Lhe mosL senslLlve lnvlLro parameLer mosL
llkely Lo correlaLe wlLh bloavallablllLy
Dev|ce factors affect|ng d|sso|ut|on
1here are several facLors LhaL musL be consldered ln Lhe deslgn of a
dlssoluLlon LesL
1 uegree of aglLaLlon
2 Slze and shape of conLalner
3 ComposlLlon of dlssoluLlon medlum
- pP
- lonlc sLrengLh
- vlscoslLy
- surface Lenslon
1emperaLure of dlssoluLlon medlum
3 volume of dlssoluLlon medlum
6 LvaporaLlon
7 Pydrodynamlcs (flow paLLern)
1emperaLure and 'slnk condlLlons' Lo be
malnLalned slnce ln vlvo 'slnk condlLlon'
creaLed due Lo lnLesLlnal permeablllLy and ln
vlvo dlssoluLlon ls a complex process meLhod
of lnLroducLlon of Lhe dosage form locaLlon of
dosage unlL sampllng Lechnlques changlng
Lhe dlssoluLlon fluld pP of Lhe medla and
1lme polnLs Lo geL dlscrlmlnaLlon eLc
- v@ ulSSCLu1lCn 1LS1lnC
,CuLLS
The OIIicial or compendial methods(USP methods) considered according to the
respective dosage Iorm are:
-Apparatus 1 Rotating basket Tablets/Capsules
-Apparatus 2 Paddle assembly Tablets/Capsules
-Apparatus 3 Reciprocating cylinder Escalating pH media
-Apparatus 4 Flow-through cell Low soluble drugs
-Apparatus 5 Paddle over disk Semisolids
-Apparatus 6 Cylinder Transdermal patches
-Apparatus 7 Reciprocating holder Transdermal patches
ett|ng of D|sso|ut|on pec|f|cat|ons
A speclflcaLlon ls deflned as a llsL of LesLs
references Lo analyLlcal procedures and
approprlaLe accepLance crlLerla whlch are
numerlcal llmlLs ranges or oLher crlLerla for
Lhe LesLs descrlbed Jhen a speclflcaLlon ls
flrsL proposed [usLlflcaLlon should be
presenLed for each procedure and each
accepLance crlLerlon lncluded
Immed|ate re|ease
3 caLegorles of dlssoluLlon LesL speclflcaLlon are
descrlbed
(l) lor 8CS class 1 and 3 drugs of rapldly
dlssolvlng producLs slngle polnL dlssoluLlon ln
01n PCl 83 released aL 13 mlnLs lf dlssoluLlon
ls rapld Lhen mulLl polnL and mulLlmedla
dlssoluLlon proflle Lo be sLudled
(ll) lor 8CS class 2 drugs ,ulLl polnL (13303
and 60 mlnLs) and mulLlmedla dlssoluLlon proflle
Lo be sLudled
(lll)D|sso|ut|on prof||e ompar|son
,oore and llanner proposed a model
lndependenL maLhemaLlcal approach Lo compare
Lhe dlssoluLlon proflles uslng Lwo facLors
f
1
(dlfference facLors) and f
2
(slmllarlLy facLors)
1he f
1
value should be beLween 013 Lo lndlcaLe
dlfference beLween Lwo dlssoluLlon proflles 1he
f2 value should be beLween 30100 Lo lndlcaLe
slmllarlLy beLween Lwo dlssoluLlon proflles Jhen
Lhe Lwo proflles are ldenLlcal f
2
100
Inv|troInv|vo orre|at|on
lnvlLrolnvlvo correlaLlon ls Lhe demonsLraLlon of Lhe
dlrecL relaLlonshlp of lo vltto dlssoluLlon raLe of drugs
and Lhelr ln vlvo bloavallablllLy Cenerally Lhe ln vlLro
properLy ls Lhe raLe or exLenL of drug dlssoluLlon or
release whlle Lhe ln vlvo response ls Lhe plasma drug
concenLraLlon or amounL of drug absorbed CorrelaLlon
ls used Lo ensure baLchLobaLch conslsLency ln Lhe
physlologlc performance of a drug producL by use of
such ln vlLro values and Lo serve as a Lool ln Lhe
developmenL of a new dosage form wlLh deslred ln
vlvo performance
1here are Lwo baslc approaches by whlch a correlaLlon
beLween dlssoluLlon LesLlng and bloavallablllLy can be
developed
1 8y esLabllshlng a relaLlonshlp beLween Lhe ln vlLro
dlssoluLlon and Lhe ln vlvo bloavallablllLy parameLers lf
Lhls relaLlonshlp becomes llnear wlLh a slope of 1 Lhen
curves are super lmposable and Lhere ls a 11
relaLlonshlp whlch ls deflned as polnLLopolnL or level
A correlaLlon
2 8y uslng Lhe daLa from prevlous bloavallablllLy sLudles
Lo modlfy Lhe dlssoluLlon meLhodology ln order Lo
arrlve aL meanlngful lo vlttolo vlvo correlaLlon
1ypes of llnear lnvitrolnvivo
orre|at|ons
1 CorrelaLlon based on Lhe plasma level daLa
2 CorrelaLlon based on Lhe urlnary LxreLlon
daLa
3 CorrelaLlon based on Lhe harmacologlcal
esponse
Leve|s of IVIV
Level A epresenLs a polnL Lo polnL relaLlonshlp beLween ln vlLro
dlssoluLlon raLe and ln vlvo lnpuL raLe of Lhe drug from Lhe dosage forms
usually esLlmaLed by a Lwo sLage procedure (Lxample deconvoluLlon
followed by comparlson of Lhe fracLlon absorbed Lo Lhe fracLlon
dlssolved) Cenerally llnear buL nonllnear are also accepLable
Level 8 CorrelaLlon based on sLaLlsLlcal momenL analysls Lxample ln
vlLro ,u1 vs ln vlvo ,1 or ,A1
Level C ln Lhls level of correlaLlon one dlssoluLlon Llme polnL (L30
L90 eLc) ls compared Lo one mean pharmacoklneLlc parameLer such as
AuC L
max
or C
max
1herefore lL represenLs a slngle polnL correlaLlon
Lxample ln vlLro 130 vs ln vlvo 1max
,ulLlple C elaLlonshlp beLween one or several pharmacoklneLlc
parameLers and amounL of drug dlssolved aL several Llme polnLs
Level u lL ls a rank order and quallLaLlve analysls and ls noL
consldered useful for regulaLory purposes
IVIV expectat|ons for |mmed|ate
re|ease products based on 8
8lCJAlvLS
1he use of lnvlLro LesLs Lo walve addlLlonal ln
vlvo bloequlvalency sLudles for some
pharmaceuLlcal producLs 1he use of ln vlLro
LesLlng Lo achleve a walver of ln vlvo sLudles ls
commonly referred Lo as a blowalver
Cl1LlA lC 8CS8ASLu 8lCJAlvL
apld and slmllar dlssoluLlon
Plgh solublllLy
Plgh permeablllLy
Jlde LherapeuLlc wlndow
LxclplenLs used ln dosage form are same as
Lhose presenL ln approved drug producL
406:;,03.0
8loequlvalence ls a comparlson of Lhe
bloavallablllLy of Lwo or more drug producLs
1hus Lwo producLs or formulaLlons
conLalnlng Lhe same acLlve lngredlenL are
bloequlvalenL lf Lhelr raLes and exLenLs of
absorpLlon are Lhe same
pharmaceuLlcal equlvalenLs are drug
producLs
LhaL conLaln ldenLlcal acLlve lngredlenLs and
are ldenLlcal ln sLrengLh or concenLraLlon
dosage form and rouLe of admlnlsLraLlon
8|oequ|va|ence 1wo medlclnal producLs are
bloequlvalenL lf Lhelr bloavallablllLles afLer
admlnlsLraLlon ln Lhe same molar dose are
slmllar Lo such degree LhaL Lhelr effecLs wlLh
respecL Lo boLh efflcacy and safeLy wlll be
essenLlally Lhe same
1PLALu1lC LCulvALLn1S
ln general Lwo producLs are consldered Lo be
LherapeuLlc equlvalenLs lf Lhey
each meeL Lhe followlng crlLerla
they are pharmaceut|ca| equ|va|ents
they are b|oequ|va|ent (demonstrated
e|ther by a b|oava||ab|||ty measurement or an
in vitro stondord)
8lCLCulvALLnCL
PharmaceuticaI equivaIence +
ioequivaIence
=
Therapeutic
EquivaIence
Why do ioequivaIence ?
For product approval, and to use as a substitute for brand name product.
When is ioequivaIence needed ?
-To establish links ("bridging) between different formulations used during
the development of a new product (e.g. clinical trial formulation and the to-
be-marketed product).
- To compare BE between test (generic) and reference (innovator) product.
- To support certain post-approval changes in approved products (e.g. a
major change in the method of manufacture).
1DD DLIGN
A slngledose bloequlvalency sLudy ls generally performed
ln normal healLhy adulL volunLeers 1he sub[ecL populaLlon
should be selecLed carefully so LhaL producL formulaLlons
and noL lnLersub[ecL varlaLlons wlll be Lhe only slgnlflcanL
deLermlnanLs of bloequlvalence A mlnlmum of 12 sub[ecLs
ls recommended alLhough 18 Lo 2 sub[ecLs are used Lo
lncrease Lhe daLa base for sLaLlsLlcal analysls
1he LesL and Lhe reference producLs are usually
admlnlsLered Lo Lhe sub[ecLs ln Lhe fasLlng sLaLe
1he bloavallablllLy ls deLermlned by Lhe collecLlon of elLher
blood samples or urlne samples over a perlod of Llme and
measuremenL of Lhe concenLraLlon of drug presenL ln Lhe
samples
CC,LL1LL? AnuC,lSLu uLSlCn
All LreaLmenLs(facLor levels) are randomly
allocaLed among all experlmenLal sub[ecLs
All sub[ecLs are allocaLed nonrepeaLlng
numbers and are randomly selecLed for Lhe
LreaLmenL Lype
AnuC,lSLu 8LCCk uLSlCn
llrsL sub[ecLs are sorLed lnLo homogenous
groupscalled blocks and LreaLmenLs are Lhen
asslgned aL random wlLhln blocks
Sub[ecLs havlng slmllar background
characLerlsLlcs are formed as blocks
andomlsaLlon of dlfferenL blocks are done
lndependenL of each oLher
Crossover ueslgns
A crossover deslgn ls usually ln whlch each sub[ecL
recelves Lhe LesL drug producL and Lhe reference producL
ln Lhls meLhod boLh Lhe LesL and Lhe reference producLs
are compared ln each sub[ecL so LhaL lnLersub[ecL
varlables such as age welghL dlfferences ln meLabollsm
eLc are mlnlmlzed
1he admlnlsLraLlon of each producL ls followed by a
sufflclenLly long perlod of Llme Lo ensure compleLe
ellmlnaLlon of Lhe drug (washouL perlod) before Lhe nexL
admlnlsLraLlon 1he washouL perlod should be a mlnlmum
of 10 halfllves of Lhe admlnlsLered drug (106) A walLlng
perlod of one week beLween admlnlsLraLlon ls usually an
adequaLe washouL perlod of mosL drugs