Optimizing clopidogrel dose response: a new clinical algorithm comprising CYP2C19 pharmacogenetics and drug interactions

Abstract

PurposeResponse to clopidogrel varies widely with nonresponse rates ranging from 4% to 30%. A reduced function of the gene variant of the CYP2C19 has been associated with lower drug metabolite levels, and hence diminished platelet inhibition. Drugs that alter CYP2C19 activity may also mimic genetic variants. The aim of the study is to investigate the cumulative effect of CYP2C19 gene polymorphisms and drug interactions that affects clopidogrel dosing, and apply it into a new clinical-pharmacogenetic algorithm that can be used by clinicians in optimizing clopidogrel-based treatment.MethodClopidogrel dose optimization was analyzed based on two main parameters that affect clopidogrel metabolite area under the curve: different CYP2C19 genotypes and concomitant drug intake. Clopidogrel adjusted dose was computed based on area under the curve ratios for different CYP2C19 genotypes when a drug interacting with CYP2C19 is added to clopidogrel treatment. A clinical-pharmacogenetic algorithm was developed based on whether clopidogrel shows 1) expected effect as per indication, 2) little or no effect, or 3) clinical features that patients experience and fit with clopidogrel adverse drug reactions.ResultsThe study results show that all patients under clopidogrel treatment, whose genotypes are different from *1*1, and concomitantly taking other drugs metabolized by CYP2C19 require clopidogrel dose adjustment. To get a therapeutic effect and avoid adverse drug reactions, therapeutic dose of 75 mg clopidogrel, for example, should be lowered to 6 mg or increased to 215 mg in patients with different genotypes.ConclusionThe implementation of clopidogrel new algorithm has the potential to maximize the benefit of clopidogrel pharmacological therapy. Clinicians would be able to personalize treatment to enhance efficacy and limit toxicity.

The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics

“…The CYP2C19∗2 allele contributes to 12% of clopidogrel variable platelets reactivity which means great portion of this variability remains unpredicted by the genotype [19, 96]. The total activity of the CYP2C19 enzyme is affected not only by the genotype but also by the interacting inducer and inhibitor drugs [97]. In other words, some EM subjects may experience poor metabolizing activity of the CYP2C19 due to concomitant administration of inhibitor drugs and vice versa; the PM subjects taking concomitant inducer drugs may experience normal metabolizing activity of the CYP2C19.…”

Thieno[2,3-b]pyridine derivatives are potent anti-platelet drugs, inhibiting platelet activation, aggregation and showing synergy with aspirin

“…Furthermore, not all patients are appropriate for this treatment, as adequate liver function is needed to metabolise these drugs into their active forms [4,10]. Of those patients that are suitable for treatment, approximately 4%-30% will be classed as 'non-responders' [13]. Currently there are several proposed reasons for clopidogrel poor/no response which include genetics (CYP2C19*2 loss of function allele, P2Y 12 receptor gene polymorphism), drug interactions, (e.g.…”

“…1 H NMR data is reported as position (δ), relative integral, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet; br, broad peak), coupling constant (J, Hz), and the assignment of the atom. 13 C NMR data are reported as position (δ) and assignment of the atom. All NMR assignments were performed using HSQC and HMBC experiments.…”

The use of oral suspension and rationally prescribing alternatives may be supplemental to the implementation of clopidogrel new algorithm comprising CYP2C19 pharmacogenetics and drug interactions

“… 12 The new clinical algorithm comprising CYP2C19 pharmacogenetics and drug interactions developed by Saab et al is very practical and beneficial in optimizing clopidogrel treatment. 1 Their study along with our perspectives may bring a more detailed guide in personalized antiplatelet therapy.…”

“…We read with great interest the study by Saab et al, 1 which shows that all patients who received combination therapy of clopidogrel and cytochrome P540 2C19 (CYP2C19) substrates require clopidogrel dose adjustment if they are not CYP2C19 *1/*1 carriers and that therapeutic dose of 75 mg clopidogrel should be tailored in patients with different genotypes (eg, lowered to 6 mg or increased to 215 mg) for the sake of efficacy and safety. We especially appreciate the new clinical pharmacogenetic algorithm they developed to optimize clopidogrel-based treatment.…”