Clopidogrel and proton pump inhibitor (PPI) interaction: separate intake and a non-omeprazole PPI the solution?

Kenngott S, Olze R, Kollmer M, Bottheim H, Laner A, Holinski-Feder E, Gross, Gross M

Description

Dual therapy with aspirin and clopidogrel increases the risk of gastrointestinal bleeding. Therefore, co-therapy with a proton pump inhibitor (PPI) is recommended by most guidelines. However, there are warnings against combining PPIs with clopidogrel because of their interactions with cytochrome P450 isoenzyme 2C19 ( CYP2C19 ). Methods The effects of the combined or separate intake of 20 mg of omeprazole and 75 mg of clopidogrel on the clopidogrel-induced inhibition of platelet aggregation were measured in four healthy subjects whose CYP2C19 exon sequences were determined. The effects of co-therapy with 10 mg of rabeprazole were also examined. Results Two subjects showed the wild-type CYP2C19 sequence. The concurrent intake of omeprazole had no effect on clopidogrel-induced platelet inhibition in these subjects. Two subjects were heterozygous for the *2 allele, with predicted reduced CYP2C19 activity. One of them was a clopidogrel non-responder. In the second heterozygous subject, omeprazole co-therapy reduced the clopidogrel anti-platelet effect when taken simultaneously or separately. However, the simultaneous intake of rabeprazole did not reduce the clopidogrel effect. Conclusion The clopidogrel-PPI interaction does not seem to be a PPI class effect. Rabeprazole did not affect the clopidogrel effect in a subject with a clear omeprazole-clopidogrel interaction. The separate intake of PPI and clopidogrel may not be sufficient to prevent their interaction.

Sujets

• Proton-pump inhibitor
• Drug interaction
• Clopidogrel
• Oméprazole
• Rabéprazole

Informations

• Publié par: biomed
• Publié le: 01 janvier 2010
• Nombre de lectures: 20
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

220 EUr J MeD Res (2010) 15: 220-224

EuRoPEan JouRnal oF MEdICal RESEaRCH

Mày 18, 2010

© I. HOLZàpfeL PUBLishers 2010

C loPIdogREl and P Roton P uMP I nHIbItoR (PPI) I ntERaCtIon : S EPaRatE I ntakE and a n on - oMEPRazolE PPI tHE S olutIon ?

1 11 12 21 S. keNNGOTT, R. oLZe, M. kOLLmer, H. bOTTheim, a. làNer, E. HOLiNsKi-FeDer, M. grOss

1 INTerNisTische kLiNiK dr MüLLer, MüNcheN, germàNy, 2 MeDiZiNisch-geNeTisches zeNTrUm Mgz, MüNcheN, germàNy

Abstract Backgr ound:dUàL Theràpy wiTh àspiriN àND cLOpiDOGreL iNcreàses The risK OfGàsTrOiNTesTiNàL BLeeDiNG. there- fOre, cO-Theràpy wiTh à prOTON pUmp iNhiBiTOr (PPI) is recOmmeNDeD By mOsT GUiDeLiNes. HOwever, There àre wàrNiNGs àGàiNsT cOmBiNiNG PPIs wiTh cLOpiDOGreL Be- càUse OfTheir iNTeràcTiONs wiTh cyTOchrOme P450 isOeNZyme 2C19 (CYP2C19). Methods:The cOmBiNeD Or sepàràTe iN-the effecTs Of TàKe Of20 mG OfOmepràZOLe àND 75 mG OfcLOpiDO- GreL ON The cLOpiDOGreL-iNDUceD iNhiBiTiON OfpLàTeLeT àGGreGàTiON were meàsUreD iN fOUr heàLThy sUBjecTs whOseCYP2C19exON seqUeNces were DeTermiNeD. the effecTs OfcO-Theràpy wiTh 10 mG OfràBepràZOLe were àLsO exàmiNeD. Results:twO sUBjecTs shOweD The wiLD-TypeCYP2C19 seqUeNce. the cONcUrreNT iNTàKe OfOmepràZOLe hàD NO effecT ON cLOpiDOGreL-iNDUceD pLàTeLeT iNhiBiTiON iN These sUBjecTs. twO sUBjecTs were heTerOZyGOUs fOr The *2 àLLeLe, wiTh preDicTeD reDUceDCYP2C19àcTiviTy. oNe OfThem wàs à cLOpiDOGreL NON-respONDer. IN The secOND heTerOZyGOUs sUBjecT, OmepràZOLe cO-Theràpy reDUceD The cLOpiDOGreL àNTi-pLàTeLeT effecT wheN TàKeN simULTàNeOUsLy Or sepàràTeLy . HOwever, The simULTàNe- OUs iNTàKe OfràBepràZOLe DiD NOT reDUce The cLOpiDO- GreL effecT. Conclusion:the cLOpiDOGreL–PPI iNTeràcTiON DOes NOT seem TO Be à PPI cLàss effecT. RàBepràZOLe DiD NOT àf- fecT The cLOpiDOGreL effecT iN à sUBjecT wiTh à cLeàr OmepràZOLe–cLOpiDOGreL iNTeràcTiON. the sepàràTe iN- TàKe OfPPI àND cLOpiDOGreL mày NOT Be sUfficieNT TO preveNT Their iNTeràcTiON.

Key words:PrOTON PUmp INhiBiTOrs, drUG INTeràc- TiONs, CLOpiDOGreL, omepràZOLe, RàBepràZOLe

I ntRoduCtIon

dUàL àNTi-pLàTeLeT Theràpy wiTh àspiriN àND à ThieNOpy- riDiNe (màiNLy cLOpiDOGreL) is recOmmeNDeD iN The GUiDeLiNes OfNàTiONàL àND iNTerNàTiONàL càrDiOLOGy sO- cieTies fOr pàTieNTs wiTh àcUTe cOrONàry syNDrOme àND/Or percUTàNeOUs cOrONàry iNTerveNTiONs. this cOmBiNàTiON is UsUàLLy prescriBeD fOr Up TO ONe yeàr. therefOre, The NUmBer OfpàTieNTs TreàTeD wiTh This reGimeN is hiGh.

uNfOrTUNàTeLy, This cOmBiNàTiON iNcreàses The risK Of UpperGàsTrOiNTesTiNàL BLeeDiNG. therefOre, mOsT GUiDeLiNes recOmmeND ThàT pàTieNTs prescriBeD àspiriN pLUs cLOpiDOGreL shOULD àLsO receive à prOTON pUmp iN- hiBiTOr (PPI) TO reDUce The risK OfGàsTrOiNTesTiNàL BLeeDiNG, e.G., The uS GUiDeLiNes [1] àND The germàN GUiDeLiNes [2]. IN The LàsT TwO yeàrs, phàrmàcOLOGicàL sTUDies hàve repOrTeD àN iNTeràcTiON BeTweeN cLOpiDOGreL àND OmepràZOLe. SUBjecTs TàKiNG BOTh DrUGs TOGeTher shOweD à reDUcTiON iN The cLOpiDOGreL-iNDUceD iNhiBi- TiON OfpLàTeLeT àGGreGàTiON [3, 4]. the phàrmàcOLOGicàL Bàsis OfThis pheNOmeNON seems TO Be The cOmpeTiTive iNhiBiTiON OfcyTOchrOme meTàBOLism, especiàLLy CYP P450 2C19 (CYP2C19). CLOpiDOGreL is à prO-DrUG reqUiriNG à TwO-sTep OxiDà- TiON By hepàTic cyTOchrOmes, iNcLUDiNGCYP2C19, 3A/5,1A2,2B6, àND2C9, TO GeNeràTe iTs àcTive ThiOL meTàBOLiTe [5]. the Key sTep iN iTs cONversiON TO The àcTive àNTi-ThrOmBOTic àGeNT is perfOrmeD By CYP2C19. HOwever, àLL PPIs àre meTàBOLiZeD TO iNàc- Tive meTàBOLiTes ByCYP2C19Or OTher cyTOchrOmes TO vàryiNG DeGrees [6, 7]. POLymOrphisms OfThe cy- TOchrOmes mày pLày impOrTàNT rOLes iN à pàTieNT’s phàrmàcOLOGicàL respONse TO cLOpiDOGreL TreàTmeNT àND The phàrmàcOLOGicàL iNTeràcTiONs OfThis DrUG [8, 9]. dàTà-BàNK àNàLyses àND reTrOspecTive cOhOrT sTUDies [10-13] hàve DemONsTràTeD àN iNcreàseD risK OfàD- verse càrDiàc eveNTs iN cLOpiDOGreL-TreàTeD pàTieNTs whO àLsO TàKe PPIs (màiNLy OmepràZOLe). HOwever, sUBGrOUp àNàLyses OfràNDOmiZeD cONTrOLLeD TriàLs [14, 15] àND OTher sTUDies [16, 17] hàve NOT cONfirmeD The àDverse effecTs OfPPI cO-Theràpy. oNLy ONe ràNDOm- iZeD cONTrOLLeD sTUDy hàs sO fàr àDDresseD This TOpic (CogEnt). uNfOrTUNàTeLy, This TriàL wàs sTOppeD eàr- Ly, àfTer The spONsOr COGeNTUs PhàrmàceUTicàLs (PàLO aLTO, Ca, uSa) DecLàreD BàNKrUpTcy. the firsT repOrTs frOm This sTUDy DiD NOT shOw eviDeNce Ofà cLiNicàLLy reLevàNT DrUG iNTeràcTiON [18]. bàseD iN This UNcerTàiNTy, BOTh The uS FOOD àND drUG aDmiNisTràTiON (Fda) àND The EUrOpeàN MeDi- ciNes aGeNcy (EMEa) hàve wàrNeD ThàT OmepràZOLe shOULD NOT Be cOmBiNeD wiTh cLOpiDOGreL UNLess “àB- sOLUTeLy Necessàry” (EMEa). the Fda wàrNiNG àLsO iNcLUDeD esOmepràZOLe. these wàrNiNGs OfThe Fda