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      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

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      Therapeutics and Clinical Risk Management

      Dove Medical Press

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          Abstract

          Dear editor 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. However, we found two points worthy of discussion and would like to share our perspectives in the following paragraphs. Use of oral suspension The conventional maintenance dose of clopidogrel is 75 mg once daily orally. There are two dosage forms and strengths for Plavix® (clopidogrel bisulfate, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Bridgewater, NJ, USA), that is, 75 and 300 mg per tablet.2 So, a practical breaking problem is encountered, that is, how can clopidogrel at a special dose (eg, 6 or 215 mg) be administered to patients? Generally, a small piece (a quarter of a pill) is the bottom line in subdividing (“breaking”) of an intact tablet because the tablet splitting process is annoying as well as being susceptible to inaccuracy of dosage.3,4 Extemporaneously compounded suspensions of clopidogrel (5 mg/mL) in a 1:1 mixture of Ora-Plus and Ora-Sweet were stable for at least 60 days when stored in amber plastic bottles at room temperature and under refrigeration.5 Also, a 5 mg/mL clopidogrel oral suspension stored under refrigeration and at room temperature maintains chiral stability as the active S-enantiomer.6 A study by Zafar et al7 shows that a 300 mg loading dose of clopidogrel given crushed via nasogastric tube provides faster absorption than an equal dose taken orally as whole tablets, but bioavailability was similar over the 24-hour period with both administration methods. Collectively, clopidogrel at a special dose (eg, 6 or 215 mg) may be administered in the form of oral extemporaneously compounded suspension. It is promising to develop a liquid pharmaceutical formulation of clopidogrel for the sake of convenience and dose accuracy. Rationally selecting alternatives We observe that the kind of proton pump inhibitor (PPI) or P2Y12 inhibitor determines the risk level of CYP2C19-mediated drug-drug interactions between classes of drugs. Clinicians should avoid prescribing omeprazole and esomeprazole for patients taking clopidogrel. The potential of proton pump inhibitors (PPIs) to attenuate the efficacy of clopidogrel could be minimized by use of pantoprazole, dexlansoprazole, or rabeprazole, rather than esomeprazole or omeprazole.8 Meanwhile, the P2Y12 inhibitors have different pharmacokinetic characteristics. The conversion of clopidogrel to its active metabolite requires two sequential oxidative steps. The first step leads to the formation of 2-oxo-clopidogrel, followed by conversion to the active metabolite. CYP2C19 contributes substantially to both oxidative steps and CYP3A4 contributes substantially to the second oxidative step. Prasugrel is also a prodrug that is activated by a two-step metabolism initiated by plasma esterases and further catalyzed by a single CYP-dependent step that primarily involves CYP3A and CYP2B6, and only partially CYP2C9 and CYP2C19. Ticagrelor undergoes extensive CYP3A4-mediated metabolism to produce an active metabolite; both the parent drug and the active metabolite can reversibly inhibit the P2Y12 receptor. PPIs use was associated with higher platelet reactivity with clopidogrel but not ticagrelor.9 There is no substantive evidence that PPIs attenuate the therapeutic effect of prasugrel or ticagrelor; therefore, prasugrel and ticagrelor may be alternatives that can escape the adverse drug–drug interactions induced by PPIs compared with clopidogrel.8–11 We reported that incidence rate of CYP2C19 poor metabolizers in Chinese populations is far higher than that in Caucasians (25% versus 2%–5%) and it is very necessary to perform genotyping of CYP2C19 prior to initiation of clopidogrel treatment in Chinese subjects.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.

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          Most cited references 10

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          Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial.

          The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49). The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events. http://www.clinicaltrials.gov. Unique identifier: NCT00391872.
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            Crushed clopidogrel administered via nasogastric tube has faster and greater absorption than oral whole tablets.

            To compare the absorption of 300 mg clopidogrel administered crushed via nasogastric (NG) tube versus whole tablets taken orally in healthy volunteers.
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              Patient experiences with the performance of tablet score lines needed for dosing.

              The aim of this study was to measure the experience of patients with score line tablets where breaking was necessary for dosing.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2016
                02 March 2016
                : 12
                : 351-352
                Affiliations
                Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China
                Author notes
                Correspondence: Quan Zhou, Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, People’s Republic of China, Tel +86 571 8778 4615, Fax +86 571 8702 2776, Email zhouquan142602@ 123456zju.edu.cn
                Article
                tcrm-12-351
                10.2147/TCRM.S103196
                4780398
                27042080
                © 2016 Chen and Zhou. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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