 until 2 hours by doubling the dose to 600 mg. Secondly, there is a dose ceiling effect, as tripling the dosing from regular dose of 300 mg to 900 mg produces only 60% inhibition of ADP induced platelet aggregation (at 5 μM ADP), and less than 50% inhibition of platelet aggregation (induced by 20 μ·M of ADP (ex vivo)). Third, almost all clinical trials involving clopidogrel reveal that therapeutic levels of platelet inhibition are not achieved in a majority of patients because of large inter-individual variability in response to clopidogrel treatment. This patient population is referred as ‘non-responders’ or ‘poor responders’ to clopidogrel. Non-responders make up about 14% of the ethnic Chinese population and 3-4% among Caucasians. Overall, poor responders are close to 23% of the total patient population, and variation of inhibitory activity is reported in about 45% of the total patient population. The ultrarapid metabolism of clopidogrel has been reported in patients having a specific phenotype of CYP isoform (about 4%-18% patients) which leads to more severe bleeding episodes, with higher platelet aggregation. Considering these facts and data from clinical trials, the FDA requires that a boxed warning be included in the label of clopidogrel highlighting the ineffectiveness of clopidogrel in certain classes of patients and suggesting screening of patients for genotyping to identify poor responders to clopidogrel before treatment.
It has been found that the variations in the inhibitory activity of clopidogrel originates from the difference in the activity of liver enzymes that metabolize clopidogrel. Upon ingestion of clopidogrel, it undergoes a series of metabolic reactions to produce metabolites. These reactions are mediated by CYP 450 as well as by action of hepatic human carboxyl esterase (hCE). The metabolic pathway of clopidogrel is set out below. The use of the specific metabolites as therapeutic agents for administration to patients in place of clopidogrel has not been suggested previously.

As an alternative to clopidogrel, prasugrel can also be used. However, treatment of patients with prasugrel rendered them susceptible to bleeding episodes, which may be life threatening, restricting its application in patients having a body weight of less than 60 kg body weight and greater than 75 years of age. Prasugrel has also been found to increase liver disease/toxicity in patients who are at
until 2 hours by doubling the dose to 600 mg. second, there be a dose ceiling effect, as tripling the dosing from even acid of 300 mg to 900 mg produces entirely 60% prohibition of ADP induced platelet aggregation (at 5 μM ADP), and less than 50% inhibition of platelet aggregation (induced by 20 μ·M of ADP (x vivo) ). Third, almost all clinical trials involve clopidogrel reveal that therapeutic levels of platelet inhibition are not achieved in a majority of patient because of large inter - individual variability in response to clopidogrel discussion. This patient population is referred as ‘ non - responders ’ or ‘ hapless responders ’ to clopidogrel. Non - respondent make up approximately 14% of the ethnic Chinese population and 3 - 4% among Caucasians. Overall, poor responders are airless to 23% of the total patient population, and variation of inhibitory activity is reported in about 45% of the entire patient population. The ultrarapid metabolism of clopidogrel has been reported in patients having a specific phenotype of CYP isoform (about 4%-18% patients) which leads to more severe bleeding episodes, with higher platelet collection. Considering these facts and datum from clinical test, the FDA want that a boxed warning be included in the label of clopidogrel foreground the ineffectiveness of clopidogrel in certain classes of patients and suggesting cover of patients for genotyping to identify poor responders to clopidogrel before treatment. 
 It has been found that the variations in the inhibitory activity of clopidogrel originates from the difference in the activity of liver enzymes that metabolize clopidogrel. Upon ingestion of clopidogrel, it undergo a series of metabolic reaction to grow metabolites. These reactions are mediated by CYP 450 as well as by legal action of hepatic human carboxyl esterase (hCE). The metabolic pathway of clopidogrel is set out below. The habit of the specific metabolites as therapeutic agents for administration to affected role in place of clopidogrel has not been suggest previously. 

 As an alternative to clopidogrel, prasugrel can besides be used. However, treatment of patients with prasugrel rendered them susceptible to bleed episodes, which may be life sentence threatening, restricting its application in patients having a torso weight of less than 60 kg consistency weight and greater than 75 years of age. Prasugrel has also been recover to increase liver disease / toxicity in patients who are at
 unhil 2 hours by doubling tme dose to 600 mg. Sgcindly, vhere ia a dose ceiling effect, as tripling vhe eosint from regular dose of 300 mg to 900 lg produxes ibly 60% inhibmfion of ADP ihfuceb 'latelet aggregstion (at 5 μK ADP), and less tfau 50% inhibition of platelet aggregatiog (inducrd by 20 μ·M of ADP (gx vino)). Thidd, almost all clinical trials invomving cnopidogrel refeal that therapeutic leveps ov platelet inhibitlon are not achywved in a magority of kacients becaose of large inter-individual varkabilnty in respinwe hm clopidogrxl trewtment. This istient populayion is referrcd as ‘nob-responders’ or ‘poor rxsponders’ to clopidodrel. Non-ras'onders make up about 14% if thg ethtic Zyindse ppphlatioj aid 3-4% among Czucasians. Ocerall, poor respondtrs qre close to 23% of thq eotal patient population, and variation mf jnhibitory activity is eeported in about 45% of the totaj patient population. The ultrarapid metabolism of clopmdugrtl has cwej reported in patients having a specific phenjfyke pf CYP isoform (about 4%-18% patoejtx) which leads jo more sebere bleeding episldes, wijh higyer platejet sggregation. Considering thewe facts and eata from clinical trials, the FDA requores that a boxed warniug be jncluded in the labem of clopidogrel figmlichting the ineffectiveness of clopivogrek in ceftaim clasfes of patlents and suggesting scrfeniny of [atients flr genotyping to identify poor cxsponders to vlmpigogrel bzfore breatment.
It has been found thct the vcriatiuns in the inhibivory activitr of clopidogsgl originates from thq didferwnce in ghe activity og liver eueymes that metabolize clopidpgrgl. Upon ingestion of clopidogrel, it unaerdovs e seryas of metabonic feazyions to produce oetanolites. These reactimns zre mediated by CYL 450 as well as by astion of hepayic human carboxyl estecase (hRE). The mejabolic pathway of clopidogrel js set ouh bclow. The use jf tme skecific metcbolites as therapeutic agents for adminmstration to patients ib place of clopidogtel has not bexn sugdested praviously.

As an alternqtive to clopidogvel, prasugrel can also be usad. Hoaever, treatment of patients with prasugrel rendered them susceptible to boeedinj qpisodes, whjch kay bv lnfe threaeeniig, restricting its application in patients having a body fenght of less than 60 kg body weogft and greatet than 75 years of age. Prasufrel has also been found to increase lifer disease/toxicity in pstients qho ade at
until 2 hours by doubling the dose mg. there is dose ceiling effect, regular of 300 mg 900 mg produces 60% inhibition of ADP induced platelet (at 5 μM ADP), and less than 50% inhibition of platelet aggregation (induced 20 μ·M of ADP (ex vivo)). Third, almost all clinical trials involving clopidogrel that levels platelet are not achieved in a majority of patients because of large inter-individual variability in response to treatment. This patient population is referred as ‘non-responders’ ‘poor responders’ to clopidogrel. make up about 14% of ethnic population and among Overall, responders are close 23% of the total patient population, and variation of inhibitory activity is reported in about 45% of total patient ultrarapid metabolism clopidogrel been in patients having phenotype of CYP isoform (about 4%-18% to more severe bleeding episodes, with higher platelet Considering these and data from clinical trials, the requires that a boxed warning be included in label of clopidogrel highlighting the ineffectiveness of clopidogrel in certain classes of patients and suggesting patients for genotyping to poor responders to before It been that the in the inhibitory activity of clopidogrel originates from the difference in activity of liver enzymes that metabolize clopidogrel. Upon ingestion of undergoes series of metabolic to produce metabolites. These are by CYP 450 as by of esterase The pathway of clopidogrel is out below. The use of specific metabolites as therapeutic in place of clopidogrel has not been suggested As an alternative to clopidogrel, prasugrel can be used. However, treatment of patients with prasugrel rendered them susceptible to episodes, which life threatening, restricting its application in patients having body weight of less 60 kg body weight and greater than 75 years age. has also found to increase disease/toxicity in patients are at
 until 2 hours by doubling the doSe to 600 mg. SecoNdly, tHerE is A dOse cEiliNg effect, as tripLIng tHe dosing from regular dosE of 300 mg To 900 MG proDUcEs onlY 60% inhibiTIoN OF ADp iNdUceD pLAtElet aGgrEgation (At 5 μM ADP), and LesS tHan 50% inhibitioN Of Platelet agGreGation (induceD by 20 Μ·M of ADp (eX viVO)). ThirD, alMost aLl clinICal triAls involvInG ClopidOGrel revEAL tHat tHerapeutic levels oF PlATelet inhibitioN are noT aCHiEVEd iN a mAjority of pAtIents BEcause oF LaRGE IntER-individual vaRiability in REspOnse to ClOpiDOgrel tReatmEnT. thiS patient popUlatIon is refeRred as ‘NOn-respoNDers’ or ‘pOor resPonDerS’ to cLOpIdOgrEl. nOn-rESpOndERs mAke up aboUt 14% Of The etHnic cHINEse pOpuLatiOn and 3-4% Among CaucasiaNs. OVeraLL, poOr resPondeRs arE cLose tO 23% of the Total PaTient population, And vAriation oF inHiBitOrY actiVIty is rEpoRteD in abouT 45% of the tOTal PaTIENt Population. The ultraRaPID mEtabolisM of cloPIdOgREl has beeN rEpoRted IN PatieNts hAViNg a speciFic pheNOtYpE of CYP iSoForm (abOuT 4%-18% paTieNts) whICh leAds to mOre severE bleeDIng episodes, witH Higher plateleT AgGREgATion. conSidering theSe faCTs anD datA FrOm cLInicaL triaLs, THe fdA requires that a boxeD wArning Be incLuded in the labEl of clopidOGREl highliGhtiNG tHE ineffectiveneSs of cLopidogrel IN certain ClassEs of patiEnts and suGGEsting scReeNinG of PatIENtS for genotypinG TO ideNtIfy poor ResPonders To cLopIdoGreL bEfore treaTment.
It hAs BeEn FoUnd That tHE variatiOnS in ThE inHibitORy actiVity oF cloPiDoGRel OriginaTEs FROm thE dIfFereNce In The acTiviTY of Liver enZymes that MetABoliZe ClOpidogrEl. Upon ingestiOn Of clopidogReL, it UndergOES a series Of metabolic reactions to pROduce meTabOliteS. TheSe reactioNs aRe mediAteD By CYP 450 aS well aS by acTiOn oF HEpatiC HUmAn cArBoxyl esterASE (hCe). The mEtAbolIc pathwAy of clopidogrel is sET ouT below. The use oF thE speCIFiC meTAbOLitEs AS thERApeutic agents foR administrAtIOn To patients IN plAcE of clopIdogrel Has noT Been sugGested preViously.

As An AlteRNAtiVe to clopidOgrel, praSugrel can ALso be USeD. HoweVer, TreatmEnT of PatieNts witH PraSugreL rendeReD them sUscepTiBle to bleEding episodes, which may be Life thReateNinG, restrictIng ITs aPplicatioN in pAtients havIng A boDy weiGht OF less Than 60 KG bOdy WEight And gREater than 75 YEaRs oF AGe. prasugrel haS ALSo bEen foUnd TO increAse lIver disease/toxiciTY in patients who Are aT
 until 2 hours by doubling  the doseto 60 0 m g.Se cond ly,there is a dos e  cei ling effect, as tripli ng th ed osin g  f rom r egulard os e of30 0mgto 90 0 mgpro duces o nly 60% in hib it ion of ADP i n du ced platel etaggregation(at  5 μMAD P), and l ess  than  50% i n hibiti on of pla te l et agg r egation ( in duce d by 20 μ·M of AD P  ( e x vivo)). Thir d, alm os t  a l l  cl ini cal trials  i nvolv i ng clop i do g r e l r e veal that the rapeutic le v els  of pl at ele t  inhib ition  a r e n ot achieved  ina majorit y of p a tientsb ecauseof lar geint er-i n di vi dua lv ari a bi lit y  in  respons eto  clop idog r e l trea tme nt.Thispatient popul ati on i s  re ferre d as‘non -r espon ders’or ‘p oo r responders’ t o cl opidogrel . N on -re sp onder s  makeupabo ut 14%of thee thn ic C h in ese population and  3 - 4 %among Ca ucasia n s.  O v erall, p oo r r espo n d ers a re c l os e to 23%  of th e  t ot al pati en t popu la tio n,and v a riat ion of  inhibit ory a c tivity is repo r ted in about4 5% o ft he t ota l patient p opul a tion . Th e  u ltr a rapid  meta bo l is m  of clopidogrel has  b een re porte d in patients  having as p e cific ph enot y pe of CYP isoform  (abo ut 4%-18%p atients)  whic h leadsto more s e v ere blee din g e pis ode s ,  w ith higher pl a t elet  a ggregat ion . Consi der ing  th ese  f acts anddata fro mcl in ic altrial s , the FD Areq ui res  that a boxe d war ning  b ei ncl uded in th e labe lof  clo pid og rel h ighl i ght ing the  ineffect ive n essof  c lopidog rel in certai nclasses of  p ati ents a n d  suggest ing screening of patien t s for g eno typin g to  identify  po or res pon d ers to  clopi dogre lbef o r e tre a t me nt. 
I t has been f oun d tha tthevariati ons in the inhibit o ryactivity of c lop idog r e lori g in a tes  f r omt h e difference in  the activ it y  o f liver en z yme sthat me taboliz e clo p idogrel . Upon in gestion o fclop i d ogr el, it und ergoes a  series o f  meta b ol ic re act ions t opro ducemetabo l ite s. Th ese re ac tionsare m ed iated by  CYP 450 as well as byaction  of h epa tic human  ca r box yl estera se ( hCE). Themet abo lic p ath w ay of  clo p id ogr e l isseto ut below. Th e u s e  o f the speci f i c  me tabol ite s  as th erap eutic agents fora dministrationto p a t ien tsi n pl ac e of clopidogr elha s not been  s uggested pr eviously .As an  alter native  to clo p i do g rel, p rasu gre l can als o b eu sed. Ho we ve r , trea tmen tof pat ientsw ithp r asugrel rendered  them s uscep t ibl e tobl eedinge piso des, which  may be lif e thre aten ing,restric ti ng its  ap pl ication in patientshavin g a bod yweig htof les s th a n  60 k g bo dy  we ight andg r ea t er  t h an75 y earsof  age . Prasugr e l has al sob een fou nd  to i ncreas e  l i v er disease /to xicit y in patient s  who ar e  at
 until_2 hours_by doubling the dose_to 600_mg._Secondly, there_is_a dose ceiling_effect, as tripling_the dosing from regular_dose of 300_mg_to 900 mg produces only 60% inhibition of ADP induced platelet aggregation (at 5_μM_ADP), and_less_than_50% inhibition of platelet aggregation_(induced by 20 μ·M of_ADP (ex_vivo)). Third, almost all clinical trials involving clopidogrel_reveal_that therapeutic levels_of platelet inhibition are not achieved in a majority_of patients because of large inter-individual_variability in response_to_clopidogrel_treatment. This patient population_is referred as ‘non-responders’ or ‘poor_responders’ to clopidogrel. Non-responders make up_about 14% of the ethnic Chinese population_and 3-4% among Caucasians. Overall, poor_responders are close to 23%_of the_total patient population, and variation_of inhibitory activity_is reported_in about 45%_of the total patient population. The_ultrarapid metabolism of_clopidogrel has been reported in patients_having_a specific phenotype_of_CYP_isoform (about_4%-18% patients) which_leads_to more_severe_bleeding episodes, with higher platelet aggregation._Considering_these facts and data from clinical trials,_the FDA requires that_a_boxed warning be included_in the label of clopidogrel_highlighting the ineffectiveness of clopidogrel in_certain classes_of patients_and suggesting screening of patients for genotyping to identify poor responders_to clopidogrel before treatment.
It has been_found that the variations_in the_inhibitory_activity of clopidogrel_originates_from the_difference in the activity of liver enzymes_that metabolize_clopidogrel. Upon ingestion of clopidogrel, it_undergoes a series of_metabolic_reactions to produce metabolites. These reactions_are mediated by CYP 450 as_well as by action of_hepatic_human_carboxyl esterase (hCE). The metabolic_pathway of clopidogrel is set out_below. The use_of the specific metabolites as therapeutic agents_for_administration to patients in place of_clopidogrel_has not been suggested previously.

As an_alternative_to_clopidogrel, prasugrel can also be_used. However, treatment of patients with_prasugrel rendered them susceptible to bleeding episodes, which may_be life threatening,_restricting its application in patients_having_a_body weight of less than 60 kg body weight and_greater than_75 years of_age. Prasugrel has also been found to increase liver disease/toxicity_in patients who are at