Pharmacokinetics and relative bioavailability of fixed-dose combination of clopidogrel and aspirin versus coadministration of individual formulations in healthy Korean men

IntroductionAlthough aspirin (ASA) is the mainstay of treatment for the prevention of recurrent ischemic stroke, the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial showed ASA monotherapy to be inferior to clopidogrel in preventing recurrent adverse cardiovascular outcomes in patients with high cardiac risks. Here, we aimed to systematically compare ASA versus clopidogrel monotherapy for the treatment of patients with stable coronary artery disease (CAD).MethodsElectronic databases were searched and studies were included if they compared ASA versus clopidogrel monotherapy for the treatment of patients with CAD and they reported adverse clinical outcomes. The latest version of RevMan software (version 5.3) was used as the statistical tool for the data analysis. Odds ratios (OR) and 95% confidence intervals (CI) were generated to interpret the data.ResultsA total number of 5497 patients (from years 2003 to 2011) were treated with ASA monotherapy, whereas 2544 patients were treated with clopidogrel monotherapy. Results of this analysis showed no significant difference in composite endpoints (cardiovascular death, myocardial infarction, and stroke) (OR 0.99, 95% CI 0.47–2.10; P = 0.98), all-cause mortality (OR 1.05, 95% CI 0.82–1.33; P = 0.71), cardiac death (OR 0.89, 95% CI 0.17–4.74; P = 0.89, myocardial infarction (OR 0.84, 95% CI 0.52–1.36; P = 0.48), stroke (OR 1.26, 95% CI 0.39–4.06; P = 0.70), and bleeding defined by the Bleeding Academic Research Consortium (BARC [grade 3 or above]) (OR 1.28, 95% CI 0.78–2.12; P = 0.33).ConclusionThis analysis did not show any significant difference in all-cause mortality, cardiac death, myocardial infarction, stroke, and BARC grade 3 or above among CAD patients who were treated with either ASA or clopidogrel monotherapy. However, as a result of the limited data, this hypothesis should be confirmed in other major trials.

Section: Discussionmentioning

confidence: 99%

Aspirin Versus Clopidogrel Monotherapy for the Treatment of Patients with Stable Coronary Artery Disease: A Systematic Review and Meta-Analysis

Ding

2019

“…All of these studies used the ABE approach for determining bioequivalence Three of these studies in Japanese and Korean subjects did not meet the bioequivalence standard for enteric-coated ASA, possibly because of the high variability of the drug [16,17,32]. Another study established bioequivalence in Korean men using the average bioequivalence (ABE) approach; however, the PK data for ASA indicated high intra-subject variability [33]. As no data from studies investigating the intra-individual variability of the primary PK parameters of enteric-coated ASA under fed condition have been reported, we assumed that the SD w was similar between the fasting and fed conditions.…”

Section: Discussionmentioning

confidence: 99%

“…As no data from studies investigating the intra-individual variability of the primary PK parameters of enteric-coated ASA under fed condition have been reported, we assumed that the SD w was similar between the fasting and fed conditions. SD w was [ 0.294 for the C max of ASA [32][33][34] under fasting conditions [35]; hence, an RSABE analysis was conducted to assess the bioequivalence of the PK parameters of ASA with high intra-subject variability, which successfully established the bioequivalence of ASA in the ASA/clopidogrel FDC. Thus, the bioequivalence of ASA and clopidogrel FDC to co-administered individual formulations under fed conditions was established.…”

Section: Discussionmentioning

confidence: 99%

“…Although there were no previous publications of bioequivalence studies for enteric-coated ASA under fed conditions, four bioequivalence studies have been conducted in healthy volunteers under fasting conditions [ 16 , 17 , 32 , 33 ]. All of these studies used the ABE approach for determining bioequivalence Three of these studies in Japanese and Korean subjects did not meet the bioequivalence standard for enteric-coated ASA, possibly because of the high variability of the drug [ 16 , 17 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Bioequivalence Study Comparing Fixed-Dose Combination of Clopidogrel and Aspirin with Coadministration of Individual Formulations in Chinese Subjects Under Fed Conditions: A Phase I, Open-Label, Randomized, Crossover Study

Ming

Kong

et al. 2020

Introduction: Simultaneous administration of acetylsalicylic acid (ASA) and clopidogrel has demonstrated efficacy in the treatment of acute coronary syndrome. Clopidogrel ? ASA in a fixed-dose combination (FDC) provides a pharmaceutical option to enhance adherence to the coadministration of dual antiplatelet therapy (DAPT). Herein, we evaluate the bioequivalence of enteric ASA and clopidogrel in an FDC compared with simultaneous administration of the individual formulations. Methods: This study is a randomized, single-center, open-label, three-sequence, three-period, twotreatment, crossover study conducted in healthy Chinese male and female subjects under fed conditions. Subjects were randomized to receive, in each period, a single dose of (1) a combination tablet containing 75-mg clopidogrel and 100-mg enteric ASA (test formulation) or (2) coadministration of one 75-mg clopidogrel tablet and one 100-mg enteric-coated ASA tablet (reference formulations) under fed conditions. Plasma samples were analyzed for ASA, salicylic acid, clopidogrel, and the clopidogrel metabolite SR26334. For ASA, the reference-scaled average bioequivalence (RSABE) analysis was conducted for C max of ASA because within-subject standard deviation (SD W) was C 0.294 for log-transformed C max. Results: The point estimate (test/reference geometric mean ratio) was between 0.80 and 1.25, and the upper one-sided 95% confidence interval (CI) for the scaled average bioequivalence metric was B 0 (-0.08). AUC of ASA as SD W was \ 0.294 for log-transformed AUC last and AUC. Estimates of 90% CIs for log-transformed AUC last and AUC ratios were within the bioequivalence range of 0.80 to 1.25 (0.98-1.08 and 1.00-1.10, respectively). For clopidogrel, the 90% CIs for the ratios comparing log-transformed C max , AUC last , and AUC ratios of clopidogrel following administration of test versus reference formulation were calculated using the Digital Features To view digital features for this article go to

“…In addition, a study with Korean subjects also did not meet the bioequivalence requirement [15]. The fourth study, performed with Korean subjects, established bioequivalence in Korean men using the average bioequivalence approach, though the data reported the pharmacokinetics of acetylsalicylic acid with high intrasubject variability [16].…”

Section: Discussionmentioning

confidence: 99%

Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Acetylsalicylic Acid in Fixed-Dose Combination with Clopidogrel Versus Enteric Aspirin in Chinese Subjects Under Fasting Conditions: A Phase 1, Open-Label, Randomized, Crossover Study

Wang¹,

Di²,

Guo³

et al. 2020

Introduction: Dual antiplatelet therapy, aspirin and a P2Y 12 inhibitor, is recommended to prevent thrombotic complications of acute coronary syndrome. Clopidogrel plus acetylsalicylic acid combination is the most commonly used dual antiplatelet therapy recommended by international guidelines and in Chinese clinical practice. Poor adherence to dual antiplatelet therapy or premature interruption of dual antiplatelet therapy is an important contributor to Digital Features To view digital features for this article go to