The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes

Abstract

AIMThe primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes. METHODSIn a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. RESULTSThe area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA 4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects. CONCLUSIONSThe additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• CYP2C19 loss-of-function alleles produce less clopidogrel active metabolite, causing less platelet aggregation inhibition, but more cilostazol active metabolite, leading to enhanced antiplatelet effects.• Cilostazol is a possible inhibitor of CYP3A enzymes that contribute to the formation of clopidogrel active metabolite.• There is a possibility of a clopidogrelcilostazol drug interaction. WHAT THIS STUDY ADDS• Cilostazol decreased the formation of clopidogrel active metabolite in CYP3A5*1/*3 but not in CYP3A5*3/*3 subjects. The antiplatelet effects of CYP2C19 EM, IM and PM after co-administration of clopidogrel and cilostazol were similar in CYP3A5*3/*3 genotypes.• Antiplatelet therapy which includes cilostazol might overcome the clopidogrel resistance caused by CYP2C19 PM in subjects with the CYP3A5*3/*3 genotype.

Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy

“…Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Acute Myocardial Infarction [AMI] Patients According to CYP2C19 Polymorphism) trial also showed that adjunctive cilostazol therapy significantly diminished the rate of HTPR in AMI patients with CYP2C19 LoF variants [23]. Therefore, DAPT plus cilostazol may benefit those patients who are CYP2C19 poor metabolizers [14]. However, in the present work, no significant differences were found between wild type and carriers of CYP2C19*2 with regard to platelet reactivity in PAD patients.…”

“…Additionally, we were unable to test a genotype-driven pharmacokinetic interaction between carriers of the CYP2C19*2 and CYP3A5*3 variants among Hispanic PAD patients on cilostazol plus clopidogrel. A previous study suggested that cilostazol might overcome clopidogrel resistance caused by CYP2C19 poor metabolizers, but only in subjects with the CYP3A5*3/*3 genotype [14]. It is postulated that patients with a CYP3A5*3/*3 genotype have decreased clearance of the active metabolite of clopidogrel, in effect compensating for the decreased formation of the active metabolite in patients carrying CYP2C19*2.…”

“…When added to standard DAPT, cilostazol inhibits the adenosine diphosphate (ADP)-induced platelet aggregation, leading to enhanced antiplatelet effects and reduced platelet reactivity on clopidogrel [13]. The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol has not been fully elucidated, but current evidence suggests a mechanism linked to CYP2C19 and/or CYP3A5 genotypes [14]. …”

Physiologically-Based Pharmacokinetic-Pharmacodynamics Model Characterizing CYP2C19 Polymorphisms to Predict Clopidogrel Pharmacokinetics and Its Anti-Platelet Aggregation Effect Following Oral Administration to Coronary Artery Disease Patients With or Without Diabetes

“…Fifteen sets of clinic pharmacokinetic data of CLOP and CLOP-AM following oral dose of CLOP to healthy subjects were included in the study. The plasma concentration-time profiles ( Figure 2 ) and corresponding pharmacokinetic parameters of CLOP and CLOP-AM following different doses of CLOP ( Table 4 ) to healthy subjects were predicted using developed model and compared with reported data ( Brandt et al, 2007 ; Kim et al, 2008 ; Umemura et al, 2008 ; Simon et al, 2011 ; Kelly et al, 2012 ; Oh et al, 2014 ; Pedersen et al, 2014 ; Holmberg et al, 2014 ; Horenstein et al, 2014 ; Kim et al, 2014 ; Kobayashi et al, 2015 ; Kim et al, 2016 ; Umemura and Iwaki, 2016 ; Song et al, 2018 ; Zhang et al, 2020 ). The results showed that most of the predicted concentrations of CLOP-AM fell within 0.5∼2.0 folds of the observed concentrations ( Figure 2F ), while the predictions for pharmacokinetics of CLOP-AM after multiple doses were deviated from the clinical reports ( Figures 2C , E ).…”

“…For pharmacokinetic validation, the variances of V max,CYP2C19 , CL int,CES1 and K t,i with standard deviation of intra-individual error were estimated using four sets of observed CLOP-AM plasma concentration-time profiles in healthy subjects ( Kobayashi et al, 2015 ; Umemura and Iwaki, 2016 ; Song et al, 2018 ; Zhang et al, 2020 ). For pharmacodynamic validation, the variances of V max,CYP2C19 , CL int,CES1 , K t,i , and k irre were also estimated with three sets of reported IPA-time profiles in healthy individuals ( Kim et al, 2008 ; Kobayashi et al, 2015 ; Kim et al, 2016 ). Then, the simulation and verification of the established population model, which based on 1,000 simulations, were performed on Pheonix WinNonlin (Version 8.1, Pharsight Cooperation, st. Louis, Missouri).…”