Increased Active Metabolite Formation Explains the Greater Platelet Inhibition With Prasugrel Compared to High-dose Clopidogrel

Abstract

Prasugrel pharmacodynamics and pharmacokinetics after a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MD) were compared in a 3-way crossover study to clopidogrel 600-mg/75-mg and 300-mg/75-mg LD/MD in 41 healthy, aspirin-free subjects. Each LD was followed by 7 days of daily MD and a 14-day washout period. Inhibition of platelet aggregation (IPA) was assessed by turbidometric aggregometry (20 and 5 microM ADP). Prasugrel 60-mg achieved higher mean IPA (54%) 30 minutes post-LD than clopidogrel 300-mg (3%) or 600-mg (6%) (P < 0.001) and greater IPA by 1 hour (82%) and 2 hours (91%) than the 6-hour IPA for clopidogrel 300-mg (51%) or 600-mg (69%) (P < 0.01). During MD, IPA for prasugrel 10-mg (78%) exceeded that of clopidogrel (300-mg/75-mg, 56%; 600-mg/75-mg, 52%; P < 0.001). Active metabolite area under the concentration-time curve (AUC0-tlast) after prasugrel 60-mg (594 ng.hr/mL) was 2.2 times that after clopidogrel 600-mg. Prasugrel active metabolite AUC0-tlast was consistent with dose-proportionality from 10-mg to 60-mg, while clopidogrel active metabolite AUC0-tlast exhibited saturable absorption and/or metabolism. In conclusion, greater exposure to prasugrel's active metabolite results in faster onset, higher levels, and less variability of platelet inhibition compared with high-dose clopidogrel in healthy subjects.

Prasugrel as Antiplatelet Therapy in Patients With Acute Coronary Syndromes or Undergoing Percutaneous Coronary Intervention

“…45 A criticism of the TRITON-TIMI 38 was that clopidogrel was evaluated by using the loading dose of 300 mg approved by the Food and Drug Administration instead of the most commonly used 600-mg clinical dose. In the past, in several trials 13,31,[46][47][48] of clopidogrel, substantial antiplatelet effects were achieved within the first 2 to 4 hours with either 300-mg or 600-mg loading doses; the effects were more pronounced when the higher dose was used.…”

“…13 Prasugrel is a novel agent in the thienopyridine class. Results of several studies [31][32][33][34][35][36][37] indicate that prasugrel has a faster onset of action, achieves higher levels of inhibition of platelet aggregation (see Figure), 31 and is associated with less interindividual variability than is clopidogrel. Because of its chemical structure, prasugrel is efficiently converted to its active metabolite and is less dependent on specific cytochrome P450 enzymes for activation than is clopidogrel.…”

Role of Platelets and Antiplatelet Therapy in Cardiovascular Disease

“…Prasugrel has shown more potent inhibition of platelet aggregation and a more consistent platelet response than standard-and high-dose clopidogrel [36][37][38] . TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) showed prasugrel to be superior to standard-dose clopidogrel in reducing ischemic events in patients with ACS scheduled for PCI, although prasugrel was associated with a significantly higher risk of major bleeding events 39) ; however, patients with stroke or TIA had net clinical harm from prasugrel and those ≥ 75 years old or who weighed 60 kg had no net benefit.…”

Metabolic Platelet Status in Patients With Stable Angina

“…При ишемиче-ской болезни сердца (ИБС) отмечается активация плазменного и тромбоцитарного звеньев гемостаза, повышение в крови маркеров воспаления, что может индуцировать тромбогенную ситуацию [5,6]. Однако метаболические процессы в тромбоцитах до сих пор остаются практически не изученными.…”

“…Однако метаболические процессы в тромбоцитах до сих пор остаются практически не изученными. В то же время, именно от активности внутриклеточных процессов зависит синтез поверхностных рецепторов, биологи-чески активных веществ, которые выделяются тром-боцитами, состояние мембран тромбоцитов, что напрямую определяет реактивность системы гемо-стаза в целом, в том числе и при патофизиологиче-ских процессах [6].…”