Pharmacokinetic interactions and pharmacogenetics of clopidogrel, prasugrel and ticagrelor

Mikko Holmberg

Research output: ThesisDoctoral ThesisCollection of Articles


The antiplatelet drugs clopidogrel, prasugrel and ticagrelor are used to treat and prevent atherothrombotic events. They inhibit platelet activation by blocking the platelet P2Y12 adenosine diphosphate (ADP) receptor. Considerable variation exists in the pharmacodynamics and therapeutic response to clopidogrel treatment due to pharmacogenetic factors and drug-drug interactions. The newer platelet inhibitors, prasugrel and ticagrelor, have been shown to be superior to clopidogrel, both in terms of efficacy and consistency of therapeutic response. Clopidogrel is a pro-drug that requires the formation of an active metabolite for platelet inhibition. Up to 90% of clopidogrel is hydrolyzed to an inactive metabolite by carboxylesterase 1 (CES1), and cytochrome P450 (CYP) enzymes CYP1A2, CYP2B6, CYP2C19, and CYP3A4 are responsible for the bioactivation process. Of these, CYP2C19 seems to be the most important in vivo according to pharmacogenetic data from patient studies and known drug-drug interactions. Prasugrel requires metabolic activation for therapeutic efficacy, as well. CES2 catalyzes the formation of a primary, inactive metabolite, which in turn is metabolized by CYP3A4 and CYP2B6 to a secondary, active metabolite. Data from pharmacogenetic and drug-drug interaction studies suggest that the pharmacokinetics of prasugrel is not as susceptible to CYP activity variation as that of clopidogrel. Ticagrelor differs from clopidogrel and prasugrel in that it does not require bioactivation. Most of ticagrelor is metabolized by CYP3A4 and CYP3A5, and drug-drug interactions with CYP3A4 inhibitors have been shown to increase ticagrelor exposure significantly. Like prasugrel, ticagrelor can be used to treat patients with high on-clopidogrel treatment platelet activity. In addition to the liver, considerable CYP3A4 and some CYP2C19 activity exist in the small intestinal wall, where they have an important role in first-pass metabolism. Grapefruit juice has been shown to inhibit intestinal CYP3A4 in vivo and affect the pharmacokinetics of several drugs. Furthermore, grapefruit juice constituents have been shown to inhibit other CYPs, e.g. CYP2C19, in vitro. CYP3A4 and CYP3A5 have generally overlapping substrate specificity and they both contribute to the total CYP3A activity. Functionally significant variants in the CYP3A4 gene include the CYP3A4*22 allele, which results in a significant decrease in CYP3A4 expression both in heterozygous and homozygous carriers. The allelic frequency of CYP3A4*22 is around 5% in Caucasians. The loss-of-function allele CYP3A5*3 is a much more common variant in the CYP3A5 gene with an allelic frequency of 94% in Caucasians. Consequently, the proportion of Caucasians with a functional copy of the CYP3A5 gene (the CYP3A5*1 allele) is low and only 10 to 15% express a significant amount of CYP3A5. This thesis comprises three randomized, controlled, cross-over pharmacokinetic and pharmacodynamic drug interaction studies, and one prospective genotype panel study in healthy volunteers. The effect of grapefruit juice-mediated inhibition of intestinal CYP3A4 and possibly CYP2C19 on the pharmacokinetics and pharmacodynamics of clopidogrel, prasugrel, and ticagrelor was studied. The effect of genetic CYP3A activity variation on the pharmacokinetics and antiplatelet effect of clopidogrel, prasugrel, and ticagrelor was studied by comparing carriers of a single CYP3A4*22 allele and carriers of a CYP3A5*1 allele to controls with CYP3A4*1/*1 and CYP3A5*3/*3 genotypes. The plasma concentrations of the study drugs were measured from timed blood samples and pharmacokinetic variables were calculated. The pharmacodynamic response was studied with ex vivo platelet function tests in blood samples. Grapefruit juice markedly inhibited the bioactivation of clopidogrel. The clopidogrel active metabolite area under the plasma concentration-time curve (AUC) was decreased to 14% of that in controls and consequently the platelet inhibitory effect was markedly reduced. In contrast, prasugrel pharmacokinetics and antiplatelet effect were only modestly altered by grapefruit juice consumption. The prasugrel active metabolite AUC was decreased to 74% of the control by grapefruit juice and only a minor reduction in platelet inhibitory activity was seen. Ticagrelor exposure was significantly increased by grapefruit juice. Ticagrelor AUC was increased to 221% of the control by grapefruit juice consumption and accordingly the interaction resulted in enhanced platelet inhibition. The CYP3A4*22 allele was associated with an impaired ticagrelor elimination, but not with a significant effect on the bioactivation of clopidogrel or prasugrel. The CYP3A5*3 genotype did not affect the pharmacokinetics of any of the study drugs. Ticagrelor AUC was 89% higher in carriers of a CYP3A4*22 allele compared to control and the antiplatelet effect was enhanced. In conclusion, the bioactivation of clopidogrel was severely impaired by inhibition of intestinal metabolism by grapefruit juice. Considering the magnitude of the effect, the mechanism of the interaction may have involved inhibition of intestinal CYP2C19, in addition to inhibition of CYP3A4. Compared to clopidogrel, prasugrel bioactivation was much less sensitive to the effect of grapefruit juice, consistent with previous drug-drug interaction studies, and probably due to the contribution of CYP2B6 in prasugrel metabolism. Ticagrelor elimination was markedly inhibited by grapefruit juice, underlining the importance of both intestinal metabolism and CYP3A4 in ticagrelor pharmacokinetics. Furthermore, the CYP3A4*22 allele was associated with significantly higher ticagrelor exposure. The concomitant use of grapefruit juice with clopidogrel and ticagrelor is best avoided due to risk of poor therapeutic efficacy and adverse effects, respectively. Genotyping for CYP3A4*22 could be used to predict ticagrelor pharmacokinetics, which could be particularly important in patients with increased risk of bleeding.
Original languageEnglish
  • Niemi, Mikko, Supervisor
  • Backman, Janne, Supervisor
Award date26 Oct 2018
Place of PublicationHelsinki
Print ISBNs978-951-51-4586-4
Electronic ISBNs978-951-51-4587-1
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 103 s. + liitteet

Fields of Science

  • Purinergic P2Y Receptor Antagonists
  • +pharmacokinetics
  • Platelet Aggregation Inhibitors
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • +genetics
  • +metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Prasugrel Hydrochloride
  • Cytochrome P-450 CYP2B6
  • Ticlopidine
  • Drug Interactions
  • Cytochrome P-450 CYP1A2
  • Platelet Activation
  • Alleles
  • Activation, Metabolic
  • Platelet Function Tests
  • 3111 Biomedicine

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