Evaluating the bioequivalence of clopidogrel generic formulations

Keywords: :

• Antiplatelet agents
• Clopidogrel
• Generics
• Risk of bleeding

Clopidogrel is one of the most commonly prescribed antiplatelet agents. Its clinical usefulness in the prevention and treatment of cardiovascular disease (CVD) has been established by several large scale clinical trials1–5.

The free-base form of clopidogrel (clopidogrel base) is unstable, owing to a labile proton in the chiral center, and susceptible to racemization and hydrolysis of the methyl ester group6. Furthermore, clopidogrel base has low water solubility and it is difficult to purify because it does not form a solid crystalline phase7. Due to these physical properties of clopidogrel base, different salt formulations have been prepared, including hydrogen sulfate, besylate, hydrochloride, resinate and napadisilate salts. The specific salt formulation of clopidogrel may influence the extent to which it is absorbed, distributed, and eliminated by the body; consequently, it determines the drug pharmacokinetic properties and therefore its pharmacodynamic potency8^,9. Thus, modifying the clopidogrel salt formulation could potentially alter its physicochemical properties and thereby may have an impact on clinical efficacy and safety9.

The innovator product of clopidogrel (Plavix/Iscover) is a hydrogen sulfate salt. It is in crystalline form and has improved solubility compared with clopidogrel base10. Following the expiration of the above name-brands’ patent, a number of generic clopidogrel salt formulations were developed and approved for the treatment of CVD patients8. The routine use of these generic clopidogrel formulations is increasing worldwide, primarily due to a significantly lower cost than the innovator product. However, it should be stated that even minor differences in the pharmacokinetic/pharmacodynamic properties of various generic clopidogrel salts could have serious clinical consequences, especially in situations where therapeutic efficacy is critical, such as early post-percutaneous coronary intervention (PCI). Despite these possible consequences, there is a continuous worldwide effort to increase the routine use of generic clopidogrel salts, mainly for cost reasons, although there is limited data in CVD patients to support their clinical efficacy and safety. In addition, some studies have raised important concerns about the pharmacodynamic potency or clinical efficacy of generic formulations of clopidogrel in comparison with the innovator salt.

Most of the studies performed to date have demonstrated that the pharmacodynamic potency as well as the clinical efficacy and safety profile of generic clopidogrel salt formulations are similar to the original clopidogrel hydrogen sulphate11–16. In contrast, a pharmacodynamic study of clopidogrel base performed in a relatively large cohort showed that this generic formulation is less effective in inhibiting adenosine diphosphate (ADP)-induced platelet activation compared with the original clopidogrel hydrogen sulfate17. The above results suggest that there may be differences in onset of action among various generic clopidogrel salt formulations administered as loading or maintenance doses. Low antiplatelet effectiveness of a certain generic clopidogrel salt may have important consequences in its clinical efficacy. In accordance with this suggestion are the results of a recent study reporting an unexpected spike in the incidence of definite acute and subacute stent thrombosis after successful PCI coincident with the use of generic clopidogrel18.

The above results are the main reason why clinicians are cautious in substituting the original salt with a generic form. Since there is a paucity of data on pharmacodynamic potency as well as on clinical efficacy and potency for most of the available clopidogrel salt formulations in CVD patients, we suggest that studies aiming to address the above issues should be performed in the near future. Furthermore, considering the numerous generic clopidogrel formulations that are commercially available today, we suggest that any clinical data or research results arising from the use of generic formulations in CVD patients should be referred to the specific product used and not generally to the generic clopidogrel salt8. Such studies will provide useful information to clinicians, will allow them to select the appropriate clopidogrel generic formulation(s) and will further encourage their routine use in CVD patients.

Consistent with the above suggestion is the study by Kim et al.19 published in this issue of Current Medical Research and Opinion. The authors present the results of a 4 week multi-center, prospective, open-label, randomized trial aiming to assess the antiplatelet efficacy and tolerability of a clopidogrel napadisilate (CN) generic formulation compared with clopidogrel bisulfate (CB). The CN salt contains 2-naphthalene-sulfonic acid monohydrate, instead of bisulfate and it is optically pure and more stable against moisture and heat than clopidogrel hydrogen sulfate20. The participants of the study were patients (men and women) aged between 20 and 85 years who had undergone PCI with a drug-eluting stent (DES) placement for >3 months before enrolment. Patients were receiving clopidogrel as an antiplatelet agent and maintained a stable condition without evidence of ischemic pain, requiring further treatment for revascularization (coronary intervention, coronary artery bypass graft or coronary angiography)19. Patients were randomized to receive 75 mg/day of either CN (n = 59) or CB (n = 56). All patients concurrently received 100 mg/day aspirin. The antiplatelet efficacy was studied using the VerifyNow assay21. The primary outcome was the difference of the percentage P2Y₁₂ inhibition between groups at 4 weeks. Secondary outcomes were: (1) baseline and change of P2Y₁₂ reaction units (PRU) between groups, (2) major adverse cardiac events (MACEs; composite of death and hospital admission for recurrent myocardial infarction), and (3) serious adverse events (AEs). There were no significant differences in the above primary and secondary outcomes between CN and CB in the study population.

Previous studies have revealed that age, female gender, diabetes mellitus, hematocrit and other variables are associated with elevated PRU values22^,23. In this study, there is a significant difference in gender between groups (p = 0.001), although the groups were randomly allocated. Therefore, the authors performed an additional covariance analysis for the change of PRU adjusting for gender and found no statistical difference between groups (p = 0.091). Importantly, the authors stated that no MACEs occurred during the study period.

Concerning the safety profile, the authors concluded that there was no significant difference in adverse events among two groups. However, we should point out that a very relevant parameter for the evaluation of the safety of clopidogrel is the rate of bleeding24, which can be estimated by a variety of bleeding scores including Thrombolysis in Myocardial Infarction (TIMI), Global Use of Strategies to Open Occluded Arteries (GUSTO), and Bleeding Academic Research Consortium (BARC) risk scores25. It is of major clinical importance that all studies aiming to compare a generic clopidogrel salt with the innovator one provide results on bleeding events. However, the follow-up period of 4 weeks used in the present study is very short and probably inadequate to permit definite conclusions on the rates of bleeding in patients treated with CN.

Indeed in the CLopidogrel trial in patients with Elective percutaneous coronary intervention for stable ANgina and old myocardial infarction (CLEAN) trial the rate of bleeding events in the clopidogrel group after PCI at 1 year follow-up was 1.3% according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) definition26 and TIMI criteria and 0.6% according to GUSTO criteria27. In the interim analysis of the very recent SCIENCE (Salts of Clopidogrel: Investigation to ENsure Clinical Equivalence) trial we observed low bleeding events at 6 month follow-up in patients treated with either clopidogrel besylate or clopidogrel hydrogen sulfate (BARC 3a; 0.3% for both drugs, p = 0.93, and BARC 5b; 0.1% for both drugs, p = 0.91)28.

The present results are consistent with a previous published study in Korean patients after coronary stent implantation. In that study, the authors concluded that the antiplatelet efficacy of CN was non-inferior to that of CB after 4 weeks of maintenance treatment. Also, no statistically significant difference was found in tolerability between the two treatment groups15. We should, however, state that both studies were performed in a Korean population. Thus, further pharmacodynamic and clinical studies are necessary in various countries where CN is available before any conclusion is drawn on the clinical efficacy and safety of this generic clopidogrel salt.

An important limitation of most of the pharmacodynamic and clinical studies on clopidogrel generics is the small study population, which does not allow definite conclusions to be drawn. Thus, further pharmacodynamic and most importantly clinical studies reporting hard clinical end points involving a relatively large number of patients should be carried out with the clopidogrel generic formulations commercially available in order to confirm their therapeutic equivalence with the innovator product. Finally, there is a wide variation in the duration of follow-up in these studies. Some of them have a short duration, thus the results may not be extrapolated to long-term treatment, especially since current guidelines recommend 12 months of dual antiplatelet therapy after DES implantation in the absence of increased bleeding risk29^,30. This issue is becoming even more serious, in light of the recent contrasting results of the clinical trials DAPT (The Dual Antiplatelet Therapy study)31 and ITALIC (Is There A LIfe for DES after discontinuation of Clopidogrel trial)32. The DAPT study demonstrated that dual antiplatelet therapy with aspirin and clopidogrel beyond 1 year after PCI and DES placement significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events compared with aspirin monotherapy, especially in good aspirin responders. However, this was associated with an increased risk of bleeding31. In contrast, in the ITALIC trial, the rates of thrombotic events and bleeding were not significantly different according to 6 vs 24 month dual antiplatelet therapy after PCI with new-generation DES in good aspirin responders32.

In conclusion, clopidogrel will continue to be widely used in CVD patients even in the era of the new more potent antiplatelet drugs (e.g. prasugrel and ticagrelor). According to various guidelines, clopidogrel can be prescribed in a wide variety of atherothrombotic disease conditions including ischemic stroke and peripheral artery disease33^,34. It also exhibits a better safety profile (lower risk of bleeding) compared with the new drugs. Furthermore, clopidogrel is now a low cost drug, due to the availability of generic formulations. The marked differences in the physicochemical properties among the various generic clopidogrel salts may have an important impact on their pharmacokinetics and therefore may influence the antiplatelet efficacy of the drug. Considering that under- or over-use of clopidogrel may result in serious thrombotic or hemorrhagic complications, we suggest that further clinical studies involving relatively large numbers of patients and with duration of at least 1 year should be performed with clopidogrel generic salt formulations commercially available today.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

J.A.G. and A.D.T. have disclosed that they have received consulting and speaker fees as well research grants from AstraZeneca Hellas, Bayer Hellas ABEE, Boehringer Ingelheim Hellas SA, Elpen and Pfizer Hellas SA. M.E.T. and I.V.N. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Notes

*Plavix and Iscover are registered trade names of Bristol-Meyers Squibb/Sanofi-Pharmaceuticals Partnership, Bridgewater, NJ, USA