I Zeng

The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response: An Analysis From the PRINC (Plavix Response in Coronary Intervention) Trial

OBJECTIVESnThis study assessed the effect of pharmacogenetics on the antiplatelet effect of clopidogrel.nnnBACKGROUNDnVariability in clopidogrel response might be influenced by polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP] family), transport proteins (P-glycoprotein) and/or target proteins for the drug (adenosine diphosphate-receptor P2Y12).nnnMETHODSnSixty patients undergoing elective percutaneous coronary intervention in the randomized PRINC (Plavix Response in Coronary Intervention) trial had platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage. Polymerase chain reaction-based genotyping evaluated polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes.nnnRESULTSnCYP2C19*1*1 carriers had greater platelet inhibition 2 h after a 600-mg dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in CYP2C19*2 or *4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C19*17 carriers (9%, 0% to 98%, p = 0.026). CYP2C19*2 or *4 carriers had greater platelet inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8% to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042).nnnCONCLUSIONSnCarriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583).

The Antiplatelet Effect of Six Non-Steroidal Anti-Inflammatory Drugs and Their Pharmacodynamic Interaction With Aspirin in Healthy Volunteers

Patients with cardiovascular disease taking aspirin and some nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have increased vascular events. This study was conducted to compare the ex vivo antiplatelet effects of 6 commonly used NSAIDs and to determine whether these agents antagonize the effect of aspirin. Platelet function was assessed by Platelet Function Analyzer 100 closure time in normal subjects in a randomized, blinded, multiple-crossover study. Platelet function was measured 12 hours after the administration of each NSAID. The NSAID was then given 2 hours before aspirin 300 mg, and platelet function was reassessed 24 hours later. At 12 hours after the administration of naproxen and tiaprofenic acid, closure time was significantly prolonged, whereas the other NSAIDs did not cause significant prolongations. Compared with placebo plus aspirin, closure time was significantly reduced when ibuprofen, indomethacin, naproxen, or tiaprofenic acid was given before aspirin. In conclusion, ibuprofen, indomethacin, naproxen, and tiaprofenic acid all block the antiplatelet effect of aspirin. Sulindac and celecoxib did not demonstrate any significant antiplatelet effect or reduce the antiplatelet of aspirin and, therefore, of the NSAIDs evaluated may be the drugs of choice for patients requiring aspirin and NSAIDs.