-*"-'--.

-- -

.Y
F -:'.ir*ia'

'iii::
WestAfricanJoumalol Pharmacy(2007),20(1)'14-22

L
NGTHE BIOEOUIVALENCEOF PARACETAMO
DETERMINI
PRODUCTSWITHURINARY EXCRETORY DATA 1J
S.ASARE.NKANSAI.I, J. K.KWAKYEAND R' K.ADOSRAKU
of Pharmacy and PharmaceuticalSciences'
Departmentot pnarmai-euicailcnemtsiry, Facutty
;;i;;;.i ieann ,fiiences' KNUS'tiKumast' Ghana

'
R6SUm6 ,,1 -..r^-^r l l n e six
a t ' r ' { i 6 a rdans
eid,t11innovateur' TylenolcForte'
^a^ ^ ^6td
a + A dtudi6e r
La biodquivalence de deux produitsgendriques dQ,paracdtamgl
la quantitd de
croisement en utilisant
hcmmesmascurins en bonnesant6dans,n" roolTniomisde de doseuniquede gdndriquesont 6t6 cod6scomme
produits
parac6tamol inchangdeexcr6t6een urineau'detirde 24heures.Les deux Les essaispr6liminaires
fabrication.
phrac.tamolcoA et paracdtamolcoB, pourr-"-.[aii.r" iour.* respectives-de. et les analysesde
ou poioJ,id ogtermination oe pbint de lusion, la dissolution
t6moignent,t,uniformitd
d'identification de
conformesaux conditionscompendiales
pourcentage emptoyanrJes m6thodesde B.p ;6fi ;i ;;"n6 des r6iultats la biodquivalence dtaient la
examindes pour caractdriser
monographie de parac€tamol.Les variablespn"ima.or,netiques d'excr6lion urinaire et le temps
incntngdeexcr6tde, le taux maximal moyen
quantit6cumulative moyennede medicament
Les uior&iires
disponibirites du Paracdtamol
retatives co A et co B se sontavdrdes106'067"
du tauxmaximat d,excr6tion. (essai/innovateur) du Parac6tamol
r" t.ri maximarr;;;";;;pp"t surinairesd'excrdtion
et 105.74%respectiveme-ni. pour taux maximal d'excrdtion6taient de 1H20+0H3'
140.06%respectivenrent. Lestemps le
coA et coB etaient136.46o/oet pur""iiuinJCon, p"r"tebmol etTylenol Forte respectivement' ll n! avait
er 1H17+0H5 heurespourte coB
1H58+0H5 de confiance de 95%' Les
statistiquement significativ"
i;;tii";;"r"ratr"r examinesdansl'intervalle
aucunediffdrence admises pour ie bioquivalence' Les
de disponibilites biologiques ont dgatement.laitpartre des iimites
valeursrelatives
6taientdoncbioequivalents au produitde r6f6rence.
deui produitsg6n6riques

products
paracetamot tngu.llol:y:l^ll^ti:, wasstudied in sixhealthvmale
+'?ffifr'"arence of twoseheric ?nd.:n of unchanged excreted
paracelamol in urineover
subjectsin a single-dose randomized using
crossover the.amount
fashion
p"r"."'i"rol coA and Paracetamol coB, to concealtheir respective
24 hours.The two genericproductswere codeJit determination'
melting.point dissolution
manufacturing sources.Preliminary sampteioenllXittn i..tt,."1f-"jT'ty of weight, paracetamol
ae 2000'rnethods yielded reiults thit complied with compendial
and percentag".ont"ntassasys'using bioequivalence were lhe meancummulative
monograph requirements. pharmacokinetic varilbt"r i".tuo io characterise
andthetimefor peak excretionrate'The relative
amountof unchangeddrugexcreted,the.meanp""[t"t" of urinary-excretion105.747orospectively' Ttre meanpeakraie of
of paracetramotco A and co B *;;; ior^o to be i06.0-6"/o and
bioavaitabitities 136.46% and 140'06% rbspectively'Timesfor
par"""aitt"r co n a1o c-oB were
urinaryexcretionralios (tesvinnovator) _of Co A' Paracetamol Co B and Tylenol Forte
peakexcretion,"t" *"r" 1.20*0.3,t.6atO.SanJ l"iZ*O'Shrs for Paracetamol parameter$ at 95% confidence interval'
tested
Therewas no statisticallysignificanidiff"r"n."in the resultof the
respectively.
values also telt *itnin limits for bioequivalence. The two genericproductswere therefore
Relativebioavailability ".."pt"d
bioequivalentwiththe referenceproduct'
generic,
comparalor andbioavailability'
proouct,pharmacokinetic
KEYWORDS: Bioequivatence,

" productsmaynotbeclinicallyequivalent'lt is thereforecritical

INTRODUCTION
-
A!r""t numberof drug products containingthe same inat pnysiciins,pharmacistsand otherswho prescribe'
of active ingredients has llooded the Ghanaian dispenieor purchasemedicines,have a betterunder-
ar;rount-
standingof genericdrugs,howtheyare testedand the true
market.One majorconcemis tho lact that the phlrrmaco-
of a drugcanvaryas a functionof theformulation' In compaiatiuevalueol formulationsubstitulionto betterlreat
kinetics adverseeffectsand/ortreatment
pro-blemsaie apt to arise whel pharmacist andavoidpossible
patients
this regard, 1 and bioequivalence
a genericdrug for a brandeddrug:product iailures.To this etfect,bioavailability
iuUstiiutes
or potentialtoxiceffeclsof the two studiescan serveas a surrogatefor clinicalproofof
Ou""rt" theth6rapeutic
1 , ,

r:
14
 wlrH URINARY
PRoDUcrs
oF iAnecernn,toL DATA
ExcnEToRY
BloEoulvALENcE
DETERMINING

t whichareparameters reflectiveof th€systemicexposure

equivalencoand an ln vivo measureof pharmaceutical The use of urine data to
tFtne drugs being studledt.
quality
' and intercheagability. i:
Bioavailability meansthe rateand extentto whichthe establishtierapeutlcequivalenceof medicineshas also
activepharmaceutical ingredient (APl) is absorbe-d from.a beenrecentlyreportedwhereths chemicaland biological
pharmaceutical dosageformand becomesavailableat the equivalence of two brandsol diazepamtabletsmarketedin'
site of action.In practice,drugconcentration-time courses Nigeriawas comparedto thatof Valium(Roche)labletss'
in thesystemiccirculation andtheareaunder Paracetamol is amongthe mostwidelyused ol all
aremeasured andanalgesia andis often
therapeuticagents forantipyrexia
thecurve(AUC)as wellas theobservedmaximumconcen-
Drugproductsareconsidered takenwithoutprescriptione'Thetabletsareproducedby most
tration(C-.-)are determined'
if theirbioavailabilities afteradministration of focalpharmaceutical industdes.A substantialin vitroquality
oioequivaiEiit
the same molardosesare similar to such a degree that asse;smentof productson ltn markethas been carried
outby the Department of PharmaceuticalChemistry Faculty
theireffects,withrespectto bothefficacyandsafety, willbe KNUSI
of Pharmacy and Pharmaceutical Sciences,
essentiallythe same and lhus, there are no relevant
differencesin terms of AUC and C*r. Types of .in vivo Kumasi,Ghana.
However,pharmaceutically equivalentproductsmay
bioequivalencestudies include pharmaco.kinetic, equivalentbecauseof
pharmacodynamic and comparative clinicaltrials.-,1. not always be therapeutically
differences in excipientsandlormanulacluring process
Oneof thesuitabletestmethodsto assessequlvalence absorption'
pharmaceulical productsis whichcan leadto variabledissolution and/or
for mostorallyadministered of
comparatiye pharmaco[inetic studies in humans , in which Theworkreportedhereis a studyol the bioequivalence
two generic paraietamol tablets (modal brands) and a
the API or its metabolite(s) are measuredas a functionof
fluidsuchas blood'plasma, comfaratorproduct, Tylenol
-equivalence Fone, with a viewto establishingr
timein an accessible biological
pharmacokinetic measutessuch therapeutic and lhe consequentpossibilityof
serumor urine lo obtbin
O* thatare reflective of the systemic exposure subsiitutingone drug product for the otherto reducedrug-
asAUCand
to &redrugF.tistaneeswherecomparativepharmacokinetic relatedhealthcarecosts.
studieshave been performedto determineequivalence
Ltdrde fueddose eomblnation of anti'tuberculosisdrug D(PERIMENTAL
fdfinulationswhere a two'period randomisedcrossover
bioequivalence study in healthymale volunleersusing Protileol Drugs
plasnradata was conducted3. The studywas designedin such a mannertnal
formulationetfectscouldbe distinguishedfromothereffeets'
The BbequivalenceTest Center,Facultyof Pharma-
ceuticalSciences, NaresuanUniversity, Phitsanulok 65000, The productswere each inspectedfor batch numbers'
performed pharmacokinetic and'relative couniryof origin,datesol manulacture and expiry'Other
Thailand,also
studiesof 20 rnt-enalapriltabletsin,healthy preliminaryteits performed includa sample'identification'
bioavailability
malevolunteersfollowinga singledosp' two'period' cross' meltingpointdeterminalion,unilormityof weight'dissolulion
over designusingplasmadata collectedover 24,hours'. test ana percentagecontent assays using paracelamol
The asseJsmentof bioequivalence of levothyroxine'sodium monographs ot BP2OOO. ThePureparaoetamoland catfeine
productsby Blakesleyis anotherinstanceof the,applica- powdJrs'usedfor preparingcalibrationcurves were also
in therapeuticequivalence physico-chemically characterised.Productswere codedlo
tion of pharmacokinetics
determinations. blindtheirmanufacturing sources.
In studiesdesignedto assessbioavailability and bio'
equivalence, it is oftenassumedthatclearance(Cl)remains In strumen tation and chromatograPhIc cond itlons
constantin thesameindividual duringall treatment periods' LibrorAEG-220Electronic Balance(Schimadzu),
(F") is therefore calculated as ERWEKAGmbHDissolution Apparatus (DT6)and Digital
Relativebioavailability
Melting PointApparatus lA
(Electrothermal 9000Series).The
AUC,*, Do*'"-
F- =
'R-AUc.r " Dose,".,1oy liquidghromatograph consistedof SpectraSystemP100
" Pump(SpectraPhysics),Spectra100 VariableWavelength
,, But,it is reasonableto thinkthatclearancemay'notbe UV Detector(SpectraPhysics),CR501 Chromatopac
c6nstantfrom periodto periodwith some degreeof Recorder(Schimadzu) and an external20pl dosingloop
intrasubject Randomized'
variability. crossoverdesignin (ModelNo. 8125-095)'Analysesweredonein the reverse
bioavailability/bioequivalence studiesthereforeminimizes phasemodeusingSpherisorb S'oODS2(10cm,4'6mm)'
theinfluence on theoutcomeof the study'
of suchvariability The mobilephasewas Methanol: 2.5%Glacialaceticacid
particularly,the estimated mean valueF^.Hence,thisstudy (15:85)at a flowrateof 1.0 mUmin'chartspeedof 5 mm/
was conductedin a randomized cross'overfashion"Since min, absorptionunit fractionscale (aufs)of 0.5 and
uiinaryexcretorydatawas usedfor lhe study'cumulative wavelength of UV detection,257 nm. Modeof elutionwas
amountof unchanged drugexcretedin urine,peakrurinary isocraticat 28"C.Internalstandardwas Catfeine.
excretionrate and the time tor peak excretionwete the
pharmacokinetic indiceslor assessingbioequivalence Materlals
because such parameters are analogous to AUC,C;* and Methanol(BDH),Aceticacid (BDH)' Potassium
'ir' L

'f,i; :i
15
WestAfricanJoumalol Pharmacy(2007)20(1)
 \
- - - - - -
\
\

''KWAKYEANDB'K'ADoSRAKU
J. K
S.ASAFE.NKANSAH,

of water'
productyll ?-9-0Tt
Calleine-(BDH)'distilled oral doseof paracetamol of waler were-administered
dihydrogenphosphats(BDH)'. prepared)'blank'urine Subsequently,2O0ml uofutls
hoursafterdosing'Drug
water(singlydistilled"t\Olt"Cnrv
person,b"l?t: drugwas at one,two,three"Jt;;; (6 am)'All
in the morning
sample(urinefrom a healthy administration was
urinesamples'withunchanged
administered),
drug ano
;;;i;i;';;; prateor iiJ anasiewanda slassor water
"'i"V"
dosing'
drug metabolites. iioo trl fourhoursatter
CatlbratlongraPh o{ pure of url1e.19.mples
A seriesof solutionsof known
concentrations Ilrlne excretlonandanalysls lromeachsublecl
HP!-'9'.The range ol Blankurine sampre!''weie-obtained
oaracetamo, n'"t
curue was Utin"- samples w-ereobtained
ffi;;;til;;
"n"'itJJ*'tn
useo toitire six'point calibration oriorto drugadministt"ion' udne samples were
of internalstandardin the emptving ih" ul"odut'
0.1-S.0pg/ml. concentratiori wasl-019/ml.A gl?ph
fne [;:;o';;;rv time-qoilts afterdrug
tinatsotutionro u" ,nroi,"i"ijr"pn"q coltected duringeachoitne totto*ing g'o' 12'0'
on'
ptitteo asainst concentrali o.s,r'0,ii' i'o' +'o'9-'9'.9'0'9'0'
;;;x ui"" t"tio'*as- i" as reportedbv Ansare'
administration: voidedduring
;l;;#
proceoule 18.0 and 24.0 hours'f'n"'uoiutt of urine volume of
il;;;;l-fi;at "do interval ;; P""';J l9::1.1^rl"
Nkansa&'KwakYeto' eachsamplins measured and recorded
urinevoidedby eachtuni"it was amount of unchanged drug
to helpin the estimationii ine
Sel*tton of drugs and subJects Samples were thenkeptin
on !ry thlnaian market excreted in thatintervai'qiiit"'
Allthe produttt theTylenol the drugsamplesin
"lt-"'u"ntly
lor use in healthcare'iri"-i"t"t"'amolCoB'and
"p""f thefridge.HPt-cwasuieJ-lo pi"" n'"i t"d€ to ensurethat
"tt"i
it"O shortly before the urinero. Dilutionor
Forte tablets were CoA tablets were "inJE
ot uncna-nFJ *ft"t"gl] intrine iamples
exDeriments.However'Paracetamol concentration the stln'dall iiirve' Since
throughthe waswithintheworkable'iingb of
obiaineddirectlyrt# in" manufacturer Factrltyof eachsubiect ths various
at
pnaimace'ticat Cnemistry' thevolumesof urinetj"ii"J"UV
Departmentor same'a commondilution
Pharmacyano pna'maclititui sti"nt"s' KNUST'Kumasi' samplingpointswerenottnl'
f a c t o r c o u l d n o t b e a p p l . r e d t o a | | t h e s a munchansed
p|es.However'
unuK, participated in the study
healthymalevolunteers sampleswerediluledtl"'n"ittt:"on:*"1t:,1io:,of Whatever
and having drugwithin thetinear retiinofthecalibrationcurve'
afterbeinginformeclot tn" putpose"9.p1-o.t:.t"1 fiol11v- that'.theconcentration
obtainedrheirconseni'i.ri"'"y
were not levelol dilutionthat wtt"Jon" "ntured
:utf:tilq as per iinur solutionwas 1opg/ml'
of good neattn and, ki-11e1:status of the internartt"no"iJin'in"
ffi;;;"J relatepeakarearatiosto
"ere
iiiLj*r l.i"*ment ("urinalysis' bloodurea nitrogen'serum The calibrationcurve*a" uieOto
liuu,iuncrion asm_easu red_9v ttryI concentration
lll,iti"Jl";Lr" "r,o- and bilirubin)' Thby were
olutamic-oxaloacetic trans"tin""t
sz v""" aseand hadbodv weishts amount
#;;;;A'"no "1
Suoietit non-smokers and Average rateol urlnary excre.ttol,11ld^cumulattve
between 50and zz ig' y^::':
at the time of thp study' ol unihangeddrug excreteclProntes obtainedby dividing
were not on any ttOit"tion'as itg was
;il ;"'t uxJ or anv.cafleine'cohtainins Rateof urinary "itit;ti"n
in a time intervalby thechange
ffi;";it "itonor the entirestudy theamountof drug
productsevendays;il 6 and throughout "tttZttO
intervJ'in" t""n of six subjectswas taken
interict with circulatory' of time in that of thetimeinterval
sinco these suostances-may no other andthevalueprotteo againiiinemiOpoint
tiver'oirenalfinction'ln addition' study' Feak'excretionrate(dDtldt)
ilt,.i^iJt*at, andthroughout the tor urinespecimen then determined'
tJrugsweretar"n t*o i""-ttt Uefore ";il;;''i""
and the time lor p"J;;;;;ii;n iate were
of unchangeddrug"me
of drugs For the cumulativeamount wasadded
Studydeslgnand admlnlstratlon randomised crossover ol drug yln.?:p^T1T"n
The studywas a iingte'dose amount ""tn inthe-previousspecimen'
divided into three to theamount "*ttti"Jin
ororugl!rcrm'red
design.The subiect""u* randomly the tor eath subiectandthe
uroupsof two'O"" gto'p' *as
given Paracetamol CoA' rhis wasdonefor 'il;;;;;;;; were
:ffi[;;;;;t"ldts';"J thJ last' rvrenor Forte tabrets' ;vJrai; t"x"n' nti inreepara-cetamol-products
Cumulative amount ol drug
betweentreatments' the investigatadina timirui't"nner'
Aftera soven'clay ol timeto fie
obtain drug
"J*i;tt'od *1t so that at the excretedwasptoneo'!;';;;;tio^
administration ot tne-proJutp .ltuuj::9
in the.panelhad received excretionProlile'
end of the study,everysuUlect fastedovernight
subje,ct
eachof the threepiliu"t*'e"ch t9:d waswithheld
for 10 hoursptiottii" "ipoittnt {g and'posture StatlsticalenalYses the calibration
forfourhours bfing Obse' PhYsicalactivity Linearreg'essilnwasused-to-construct
"tt"t is" much as possible to lirnittheir *^?" q" sbtisticaltool
were also controtteJ curve.Analvsi.or uJti"nJJ iaNonq
ttowandmotility'Fluidintake in thepharmacokinetic
etlectson gastroint;;;utoo'o to respectivery
was also ,"gutut"o'i;'ffiine
cnancetof.fluidprofoundly "otp"t"-i"i"tiont of drug excrotedin 24
before the variablesttne cumtirliiu" "to"tt t-1t:3^othetime'for
Ht19"'-^u.L^hout
inlluencinggastricpttti-g;' was made to drink hours,peakot me u?ina-rV-eioe19i
administrationor u 5J*' iuch subiect
single oeakexcretion rate)amongthe threeproducts'
a 1'09
200m1of water.EaJil'uUi-eatnen'ingested
(200n 20fl)
WestAficanJoumalofPharmacy
16.
 t,i

DATA
OF PARACETAMOLPFODUCTSWITHURINARYEXCRETOFIY
DETERMININGBIOEOUIVALENCE

'i,: o/o)lor
FESULTSANDDISCUSSION than twice the maximumpermissiblelimit (t10
i Multisource pharmaceutical productsneedto conlorm uncoated tablets, both Paracetamol CoA and CoB could be
to:ithesamestandards of quality,efficacyand safetyas saidto havefulfilled the uniformity of weightrequirements
requiredof theoriginato/scornparator product.Specifically, of BP 2000.
themultisource productshouldbe therapeutically equivalent All the extracted paracetamol fromeachproducthada
and interchangeable with the comparalorproduct;Testing meltingpointof about,169€whichis the BP2000reterence
the bioequivalence betweena productand a suitable for the monographof paracetamoltablets. Respeclively.
pharmaceutically equivalenlor a pharmaceulical alternative Paracetamol CoA,Paracetamol CoBand TylenolFortehad'
in a pharmacokinetic studywitha limitednumberof:stt61""r. meltingrangesol 168.i1-169.1€, 168.5'169.1€and168.9-
is onewayof demonstrating therapeutic equivalence without 169.SC.The preliminary assegsments lhereforesuggested
havinglo performa clinicaltrialinvolvingmanypatients"In that the drug productsused for the study were pharma'
sucha study,anystatement aboutthesafetyandetficacyof ceuticalequivalents.
lhe testproductwillbe a prediclion basedon meaEuiement The referenceparacetamol powderwas adequately
of systemicconcentralions, assumingthat essentially, characterised in termsof identification andpercenlage purity
similarplasmaconcentrations at the site of actionrjimplies according to BP 2000.Thesamplegavea violetcolourthat
similartherapeutic outcome.Thus,bioequivalence study did not turn red after followingthe Liebermann's test
providesindirectevidenceof the efficacyand safetyol a described in the BP This observation meant that the sample
multisource drug product2. was paracetamol and not phenacetint3. The assayvalue
. ft is a WHOrecommendation that potencyandin vitro (99.92%) alsofellwithintherangeolthe BP (99.0-101.0%).
dissolutioncharacteristics of a genericand innovator The meltingpointwas also around169qC(169.1-170'0).,
pharmaceuticalproducts be ascertainedp4ibr to All thesetestsconlirmedtheauthenticity ol the purepowder
performance of an equivalence study.ln addition,thecontent for use in quantitativeevaluations.Calibrationcurve
of the API ol lhe innovatorproductshouldbe closelo the constructedwith lhe Puresamplegave a linearcurvewith
labeldaim, andthe differeneobetweentwo productsshould coetficient of correlation (r?),0.9998,implyinglhatpeakarea
preferably be noi rnorethanz 5"k2.FromTabiei, nc iwo :-alioccrrelatediineariywith concentration oi paracelamol
prodr.lctsh the shdy d$feredby morethan*57owith tqspect (Figure1). All concentrations of paracetamolin eacfi urine
to !heAP!.BespectiveM Paracetamol CoA,Paracetamol CoB sampleanalysedwas thereforeinterpolaledfrom the
andTylenolForte(innovatodhadmeanpercentage contents standardcurve.
of 103.32,104.90and 104.67,justifyingthe suitabilityof Thesensitivity, accuracl/iprecisionandvalidationof the
drugsamplesusedlor the eguivalenceevaluation.Eachof bioanalyticat methodappliedin the study have been tully
the drug productsalso compliedwith the BP 2000 mono efucidatedto. Figuresza-c arc typical chtomatograms
graphrequirements for the identification of paracetamol, demonstrating that the assay ol paraae&amol'h the urine
uniformity of weightandmeltingpo;ntdeterminations.'None samplesdid'not sutferfrom inlerferenceby-endogenous
of the twentytiabletstestedtor TylenolForte(unifornrityof compdunds,lndicatingtha selectivityor speciticityof the
weight)deviatedby morethant 5% whichis the maximum analyticalprocedure.Paracetamol had a meanretention
pelmissible limitfor variationsin weighlof 19 out of 20 . h i l e t h a t o f c a l f e i n ew a s
t i m e o f 2 . 6 1 t 0 . 1 m i n sw
uncoated tabletsof averageweight250 mg or morel2.One 11.98t0.7mins.
tableteachof bothParacetamol CoAand Paracetamol CoB Thestudydesignwaslo minimise variability withinand
deviatedlrom their respectiveaveragemassesby,-5.35 betweensubjects.The singledose study was preferredto
and7.797orespectively. Sincethesedeviationswergless multiple-dose becaussthe single-dosestudiesare

Tabtet: Proflleof paracetamot

productsusedtor the study

Drug Strength Batch Expiry oh Mean!" Counlry

[4anufacluring
Sample (ms) Number : Date Date Conlenl Dissolved of Origin
;. Found' at 45mins'.
Paracetamol
CoA 500 DO6510 'Notavailable 05/0s 103.32 86.12 Ghana
TylenolForte 500 9 9 E S 1 2 3 ii" 0s/99 05/04 104.67 91.40 Switzerland
i:'
:.,ia (CilagLtd.)
Paracetamol
CoB ':' 8N511 07t0'l 07106 104.90 78.84 Ghana
,|:
PureParacetamol 0 1 0 1 1 2 3 .Notavailable Not available 99.92 Germany
powder (Chemcon
GmbH)
(-) impliesnotapplicable
'Anblysiswas done in July2002

West African Journal of Pharmacy (2007) 20(1) 17

 \
1
\,
\

J, K, K\{AKYEANDR' K.AoosRAKu
s. A$ARE-NKAxS'AH,

t.4 Y=0.?393x-
Gm37
t .:r'

1.2 R*=0.9998
o
(E
I
E
o
o 0.8
ta
G
(,
o. 0.6
o
o
= 0.4
0.2
.t , ;i,!: 'lr}itrilli'|t.trlir,

, 0
,.)ir(,:i.'trl' r'
2,, 3 ,4 i , , r l ; ' p ; g l r . i t : . ' ,;
'
ParacetamotConcentrationug/ml ,;!rii|'i !.'i' .'
. , .r f . , ; 1 . ! / i ; . , i ',

'
l.'it
":

Fig. 1: Calibrationcurvefor pure paracetamolpowdel , , " ' , , t ' , t :

t,.'ltt(,!',:i: I
,.
;;, .i,i i.iil itr,r
. , . . : t : r . , : .j ! . ,

the variabililywas not statistlctillyslgnllicgnt.The cqmu.lative

considered to providemoresensitivsmeasurements'of
releaseof API from the pharmaceutical product into the amounlof unchanged oiclgtqdprolile(Figure4) also
drug
the drug depictedtne dxteniof paricotamolexcr,e.ted unchanged in
systemic circulation2.Co-administrationol foodwith
productsmayalsoinlluencethe plasmadruglevelthrough ,rine acrosr the products.,9,h-c..9 !-lg,extentof drug
absorptioncorrelateswiln qllF,hatipp?, yvhenthe drug.is
variableabiorptionr',hence,the studywas conducted glimtqaib{',thg plasml concentration
urong fastedindividuals to enhancethe reproducibitity ot completely
pharmacolinetic "sseniially
approaches zero andthe Fag.nHm ar4otlnlof drug excreted
drug bioavailability and consequently,
bioiqulvalence. lt h-asalsobeenreportedthatwherslurinary in ihe urinebecomeslpttep$yegI,![i,|U,9,
The data irom thg,.Qigp9.{y9le-lqe studies,were
excretionis measuredin a single-dosestudy,it is necessary of excretion
lo collecturjnefor sevenor,morehalf-livesrs. The'mean subjegted to non'coinpa'riiirglitai.inqly$sr,
flatg
elimination half-lifeof paracetamol is 2.5 hrs.'3Collecting and cumulativeahbunt excietedtiine curveswere plotted
urinesamplesfor24 hourswasmorethansevenelimination for eachseriesof drugassays.lt was lromtheseplotsthat
theparameters indicaGdin Table2 weretletermined' These
to ensureadequateexcretionof paracetamol'
half-lives were
Figure3 describesthe completeprofileoI {ate of paramelers,exceptthe relativebioavailability,
to a subjecled to analysisof varianco (ANOVA) (Table 3)' At 95%
excietidnwhereratebf excretion steadilyincreased,'"bot
interval(Cl)rs,there was no significantdifference
peak and declinedto a baseline,depictingldgquate "oniid"nc"
betweenthe variables assessed (Table3)'
elimination of the drugs.The figurealso simulatbsthe
curyewhereboththe absorption The90%clearance of cumulative amountof qnchanged
plagmaconcentration'lime
phases areclearlyshownmakingit possible drug excretedratios (tesUinnovator) of both Paracetamol
andelimination 106.06%and'lO5'74o/"
to,usethe i:eakexcretionrateand timefor peakexcretion Co-Aand Co B wererespectively
(analogous
ratewhichcomparatively are analogousto C*, and tru as ft-able2). The ratioslor the peakexcretionrate
In additionto io Cmax)of the same set of products were respectively
variablesfor assessing bioequivalence.
the
the physiological differences(gastrointestinal, liver and 136.46{ and 140.06%. Basedon the Europeanbio-
in the'iateof equivalence guidelines, the 90% Cl ratiosol the tested
XiOnLvf amoig the subjects,the variations
products variablesshould be between 80-125%for the relative
excreiionprolileamongstthe three paracetamol for the peakexcretionratefor
couidbe due to the differences in manufacturing plocess bioavaifability and7O-143"h
theirrespective two producisto be declaredas bioequivalentl' Both
andselection of excipients whichcould affect
Paracetamol Co A and Co B had respective values thatfell
releasskinetics.However, fromTable3, the intersubiect

WestAfricanJoumal ot Pharmacy(2007)20(1)
18
 DETERMINING
BloEoulvALENcE pRoDucrswrrH uRrNARy
oF PARACETAMoL ExcREToFyDATA

>.
./)
o

o0 0.2
q)

0.1

Flg.2 (a): Chromalograrnot btank urtne

0.4
>r
ah

s 0.3

o0
6 0.2

0.r

19
 .l{

a
i{

:3

q
S.ASAHE-NIfiNSAH,J. K. KWAKYEANDR. K.ADOSRAKU
I
a

.J
t

Paracelamol
t
0st
I Caffelne
04+
'. db ll
il
Em +
F r
I
' i; ll

,, 1rl
ri,

/v,
.:.i ll

c g
I
l 7 .i! '
'ir'-'
II
F' a2 f ,...ti,
,,it
? 5 | t l
L\-*--{---l\{.
0 l t - -lrl
I
I

Retentlon Tlme (Minutes)

Flg.2 (c): Chromatogram of reference paracetamol and cellolnc

Table 2: Pharmacoklnetic paramdlers for the assessment of bioequivalence

Parameter Producls
TllenolForte
Cumulativeamountexcreted(mg) 53.01t 9.33 5 2 . 8 5t 1 1 . 5 3 4 9 . 9 8* 7 . 1 4
Peakexcretionrate(mg/hr) '12.50
t 4.33 12.83t 6.05 9.16 t 2.09
Timefor peakexcretion
rate(hr) 1 . 2 0x 0 . 2 7 1.58t 0.49 1 . 1 7x 0 . 5 2
RelativeBioavailability
(%) 106.06 105.74

Table3: Statisticalanalysisof bioequivalencevariables

parameter
Pharmacokinetic Estirnate of variance Frrr.*ro,.o Fts, z ot..r Commenlon Ho
Within sample Between sample
Cumulativeamountexcreted(mg) 9 0 . 3 2 3: i 8.751 10.32 19.431 Valid
Peakexcretionrate(mg/hr) 19.716 , 12.367 1.59 19.43 Valid
Timefor peakexcretionrate(hr) 0 . 19 4 : r 0.157 1.238 19.43 Valid

n V/est African Joumalof Pharmacy (2007) 20(1)

 DETERMINING
EIOEOUIVALENCE
OFPAFACETAMOL
PRODUCTS
WITHURINABYEXCRETORY
DATA

t4

ol
tr t2
o
5
(f
! t0
tr
"9
o
(,
L
8
x =FParacetamol
ltt CoA
F --r-- Paracetamol
o CoB
€ 6 -r- Tylenol Forte
3
o
o A
q, t
G
o
ot
o
o 2

i::ii!
i:t,! Tinr (hr)
iil
::l
-.ijj
.+.1 Fig-li Averagerate of urinary.excretionof bran{q of
Rgracefamot
iY
li!t .
',,3 :
1 .

. i l
;191
.r{t
:.jl

I'J
rG
tl
;.i|
': ! 60
o
crl
c
ag
.c
o 50
:
oG;
F E 40
J

9 6
c E --i-Paracetamol CoA
o E
30
.sE
= 6
*r*-Paracehmol
CoB
= o TylenolForre
Eo. 20
o
o
ol
.!
l0
o

0 .
0 5 1 0 l s 2 0 2 s 3 0
Time (hr)
Fig. 4: Cumulativeurinary excretionof paracelamol
producis

West Afican Joprnat of pharmacy (2007) 20(t)

21
 .-*- * ,oa, *.-,*t

:
S.ASARE-NKANSAH,
J. K.KWAKYE
ANDR.K.ADOSRAKU

withineachspecifiedrangeof acceplance.Srncelncrewas in bioecluivalence studios Abdailah, (1998).

f-t.'y'. J.
no statistical
dilferencebetweenlhe pharmacokinetic PharmPharmaceut Sci( www,ualberta.cal-csps), 1(Z):
variables
tested,theparacetamolproducts
usedfor'lhestudy ou-os.
couldbe describedas bioequivalent. :
7 . S h a r g e l ,L . a n d Y u , A , B , C . ( 1 9 9 3 ) .A p p l i e d
CONCLUSION Biopharmaceutics and Pharmacoklnotics, 3rd ecjition,
Paracetamol CoA and Paracetamol CoB were bio- Appletonand Lange,Nonvalk,CT.pp 200-ZO,l.
equivalentwiththe referenceproduct,TylenolForte;:
These
productsare thus therapeutically equivalentor inter_ 8. Ogunbona,F.A.,Adedoyln, A.A. (19S5).
P.A. & Olaniyi,
changeable. Healthcare professionals can therefore Comparative bioavallablllty
studleson brandsof
substitute
one for the other. diazepam
tablets.Afr J ModMedSci.,14(1-Z):21-25.
,tl
9. Katzung,G B.(1999). pharmacology,
BasicandClinicat
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: l"
luberculosis drug formulations
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V.A. (2005).Currentmethodotogy
to'Fssess 15. Guidancefor Bioavailability
andBioequivplence
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n WestAlrican Joumal ot Pharnacy (2@7) 2O(t)

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