Antiplatelet drugs belong to the class of pharmaceuticals that inhibit platelet activation and thereby suppress arterial thrombus formation. They are widely used for primary and secondary prevention of atherothrombotic diseases including coronary heart diseases, ischemic strokes and peripheral arterial diseases. These drugs are broadly classified into two categories: (1) inhibitors of the platelet activation signal-transduction system, and (2) stimulators of production of inhibitory signals such as cAMP and cGMP. The first category comprises ADP receptor (P2Y₁₂) antagonists including ticlopidine, clopidogrel and prasugrel; the serotonin 5-HT₂ receptor antagonist sarpogrelate; the cyclooxygenase-1 inhibitor aspirin; and eicosapentaenoic acid. The second category comprises prostacyclin analog, the cyclic nucleotide phosphodiesterase (PDE)-3 inhibitor cilostazol, and the PDE-5 inhibitor dipyridamole. Drugs in the second category stimulate vasodilation, as well as inhibit platelet aggregation. Current clinical trial evidence favors the use of aspirin, clopidogrel and cilostazol as first-line agents in the majority of patients with vascular disease. Clinical trials evaluating novel antiplatelet drugs will impact the direction of future practice.

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In this study, we investigated whether the polymorphism of CYP2C19 affects the formation of active metabolite (AM) of clopidogrel and the antiplatelet effects of the AM in healthy subjects. In this single-dose study, 47 subjects were given 300 mg clopidogrel orally. The mean AUC and C_max of the AM differed significantly (P<0.05) between the extensive metabolizers (EMs, n=18) and the intermediate metabolizers (IMs, n=20), and also between EMs and the poor metabolizers (PMs, n=9). Moreover, the pharmacokinetic parameters of the AM correlated well with the inhibition of ADP-induced platelet aggregation (IPA) and the change in vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Individual differences in antiplatelet effects of clopidogrel were detected adequately by measuring IPA using aggregometer and VerifyNow and by analyzing the change in VASP phosphorylation. The CYP2C19 pharmacogenomic status is a determinant for AM formation and antiplatelet effects of clopidogrel in healthy subjects.

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Low-dose aspirin (LDA) is the mainstay of prophylactic antiplatelet therapy for patients with cardiovascular and cerebrovascular diseases. LDA induces gastrointestinal mucosal injury directly and indirectly via reduced mucosal prostaglandin by inhibition of cyclooxygenase. Dual antiplatelet therapy, such as a combination of LDA and thienopyridine derivatives, is often used after implantation of a drug-eluting stent. However, dual antiplatelet therapy significantly increases the risk of gastrointestinal bleeding. Proton pump inhibitors (PPI) reduce the risk of gastroduodenal bleeding in patients receiving dual antiplatelet therapy but attenuate the antiplatelet effect of clopidogrel, the most commonly used thienopyridine derivative. The optimal prophylaxis strategy for gastrointestinal bleeding in patients receiving antiplatelet therapy remains to be determined.

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Previous studies clearly demonstrated the efficacy of antiplatelet drugs for secondary prevention of atherothrombosis in patients with atherosclerotic diseases. However, clinical events still occur in some patients despite receiving conventional antiplatelet therapy. Recently several new drugs have been developed to further improve the efficacy of antiplatelet agents. Prasugrel, ticagrelor and cangrelor are new P2Y₁₂ receptor antagonists that possess better metabolic profiles than clopidogrel, and show more potent and consistent efficacy for the inhibition of platelet aggregation. In patients with acute coronary syndrome (ACS), prasugrel and ticagrelor were superior to clopidogrel in reducing cardiovascular events, although intravenous cangrelor did not show superiority over clopidogrel. The thrombin receptor antagonist SCH-530348 showed a trend to reduce ischemic events without significantly increasing major bleeding in patients with ACS receiving both aspirin and clopidogrel in a phase 2 study. Results of ongoing clinical trials will provide further insight on the clinical benefits of these new antiplatelet drugs for the treatment of atheroembolic diseases.

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We performed a placebo-controlled, double-blinded, 3-way cross-over study to examine the effect of tebipenem pivoxil (TBPM-PI), a novel oral carbapenem antibiotic, on QT interval in 12 healthy male volunteers assigned to three groups: recommended clinical dose, double of recommended dose, and placebo control. TBPM-PI administration did not influence QT intervals, but slightly shortened RR intervals. When the QT intervals were corrected for RR, the corrected QTc-B intervals (=QT/RR^0.5) and QTc-F intervals (=QT/RR^0.33) in the TBPM-PI groups were prolonged at several time points due to shortened RR interval after dosing, compared to the corrected QTcs intervals in the control group. However, the QT intervals corrected with a factor“n”estimated before dosing from all subjects (QTc-N interval=QT/RRⁿ) and the QT intervals corrected with a factor“ni”estimated from individual subjects (QTc-I interval=QT/RRⁿⁱ) were not significantly prolonged at all time points compared to the placebo group. We therefore concluded that TBPM-PI has no evident effect on QT interval prolongation.

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We analyzed the current status of clinical pharmacokinetic (PK) studies in new drug applications (NDA) by evaluating 17 cardiovascular (CV) drugs that were approved between 2000 and 2007 in Japan since CV drugs were one of the largest categories to be submitted. All summaries of data had been submitted by applicants and were freely accessible on the website of the Pharmaceuticals and Medical Devices Agency (PMDA). The clinical PK studies were divided into 12 categories: single-dose, multiple-dose, food-effect, elderly, gender difference, mass balance, absolute bioavailability, target patients, liver impairment, renal impairment, drug-drug interaction, and population PK studies. The median number of clinical PK studies per new molecular entity (NME) excluding single-dose, multiple-dose, and food-effect studies was 13.5, and foreign data accounted for 86% of the study results. A relatively high proportion of PK studies in Japanese subjects were observed in elderly volunteers and target patients; however, a dependency on foreign data was noted in the other PK study categories. The effect of the guidance“Clinical PK Studies of Pharmaceuticals”by the Ministry of Health, Labour and Welfare on implementation of clinical PK studies could not be fully assessed, since there were only three NMEs approved prior to issuance of the guidance. The median number of clinical PK studies per NME was approximately three times higher for drugs for lifestyle-related diseases than that for other drugs. In recent NDA reviews by the PMDA, the trend to emphasize a relationship between PK and safety with respect to drug-drug interactions and/or special populations was noted.

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To promote the use of generic drugs and reduce healthcare costs, the Japanese government revised some rules related to generic drugs in April 2008, such as the medical treatment fee. Following this revision, generic drug use in pharmacies and pharmacists' attitudes on generic drugs were expected to be considerably changed. This study examines the generic drug use in pharmacies and pharmacists' attitude toward generic drugs by means of a questionnaire survey, undertaken to identify and clarify the problems in their use.
An anonymous questionnaire survey was conducted in 627 pharmacies, which were randomly selected from a total of 1,244 community pharmacies in Shizuoka prefecture (period of collection: September 16 to October 31, 2008).
A total of 284 (45.3%) questionnaires were collected. The results revealed that 82.8% of the pharmacies charged an additional fee for the preparation of generic drugs. The preparation ratio of generic drugs in August 2008 (41.1%) was significantly higher than that in August 2007 (32.9%). Further, 69.0% pharmacies answered in the affirmative to the following item: “The 2008 revision will facilitate the preparation and substitution of generic drugs.” On the other hand, for the item about the use of generic drugs in the future, 71.4% pharmacies answered“Under consideration” or “Not using generic drugs positively.”Many pharmacies indicated certain limitations in the use of generic drugs and expressed the necessity for improvements to be made by the government and the generic drug industry; they responded in the affirmative on the items“Increase in the number of accumulating stocks” (94.7%) and“Insecurity in the quality of generic drugs” (69.7%).
The findings revealed that despite the increased use of generic drugs, many pharmacists mistrust generic drugs owing to disadvantages such as an increase in the number of storing items. In the future, it will be necessary to reduce this anxiety and raise pharmacists' incentive for keeping supplies of these drugs by improving the accumulating stocks of generic drugs through legal intervention.

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A PhRMA Working Group on adaptive clinical trial designs has been formed to investigate and facilitate opportunities for wider acceptance and usage of adaptive designs and related methodologies. A White Paper summarizing the findings of the group is currently in preparation. This article is an Executive Summary of that full White Paper; it summarizes the findings and recommendations of the group. Logistic, operational, procedural, and statistical challenges associated with adaptive designs are addressed. Three particular areas where adaptive designs can likely be utilized beneficially are discussed: dose finding, seamless Phase II/III trial designs, and sample size reestimation.

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