Spaced pa 32540 with clopidogrel cuts pharmacodynamic interaction compared with concurrent administration

Spaced pa 32540 with clopidogrel cuts pharmacodynamic interaction compared with concurrent administration

Dual antiplatelet therapy (DAPT) with PA32540 and clopidogrel demonstrates a decrease in drug-drug interaction when spaced 10 hours apart in healthy volunteers, according to phase 1 results released at the American Heart Association (AHA) Scientific Sessions 2010.

PA 32540 is an investigational coordinated-delivery tablet of immediate-release omeprazole (40 mg), layered around enteric-coated aspirin (325 mg). The product was developed to provide the cardiovascular benefits of aspirin with a lower incidence of gastric ulcers than enteric-coated aspirin alone.

The investigators say that their findings suggest that administration of immediate-release omeprazole (contained in PA 32540) plus clopidogrel may be associated with a different pharmacodynamic profile than delayed-release omeprazole plus clopidogrel. The distinction may be important in patients who may benefit from DAPT therapy but are at increased risk of ulcers.

Paul Gurbel, MD, Director of Cardiovascular Research at the Center for Thrombosis Research at Sinai Hospital of Baltimore, and colleagues conducted a study to evaluate whether PA32540 would affect the antiplatelet properties of clopidogrel during concomitant or spaced administration.

In prior studies, DAPT therapy with clopidogrel plus aspirin reduced the occurrence of ischemic events in stented patients, Dr. Gurbel said. Co-administration of proton pump inhibitors with DAPT decreases gastrointestinal bleeding and was recommended in the 2008 expert consensus document issued jointly by the American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the AHA.

However, new evidence of a decreased pharmacodynamic effect and an increased occurrence of ischemic events with a proton pump inhibitor (PPI) plus clopidogrel (mostly delayed-release omeprazole) was highlighted by a Food and Drug Administration advisory and a European Medicines Agency public statement prompting an update in the 2010 ACCF/ACG/AHA consensus document. The update notes that PPIs are appropriate in patients with multiple risk factors for gastrointestinal bleeding who require antiplatelet therapy.

The three-arm crossover study enrolled 30 healthy adult volunteers.

Treatments included:

  • A) clopidogrel 300 mg plus enteric-coated aspirin 325mg on day 1, and clopidogrel 75 mg plus enteric-coated aspirin 325 mg on days 2 through 7
  • B) clopidogrel 300 mg plus PA32540 on day 1, and clopidogrel 75 mg plus PA32540 on days 2 through 7
  • C) PA32540 in the morning plus clopidogrel 300 mg more than 10 hours later on day 1 and PA32540 in the morning plus clopidogrel 75 mg 10 hours later on days 2 through 7.
Patients were initially randomized to treatment A or B and then crossed over to the alternate treatment. They were administered treatment C following a second washout period. Each treatment period was separated by a 14-day washout period.

The primary endpoint was the percent inhibition of platelet aggregation (IPA) one hour after morning dosing on day seven of each treatment period.

Results showed that with synchronous administration of PA32540 and clopidogrel, the non-inferiority margin of 10 percent IPA was exceeded. When PA32540 and clopidogrel were spaced apart by at least 10 hours, the non-inferiority margin was met.

Dr. Gurbel said that additional investigations of PA32540 are indicated in patients requiring clopidogrel and aspirin and omeprazole therapy

The study was funded by Pozen, Inc. in Chapel Hill, North Carolina.

Jill Stein is a Paris-based freelance medical writer.

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Section Issues On Medicine: Cardiology