title: Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus.
abstract: BACKGROUND
  A limitation of aspirin is that some patients, particularly those with diabetes, may not have an optimal antiplatelet effect.
  
  
  OBJECTIVE
  The goal of this study was to determine if oral bioavailability mediates nonresponsiveness.
  
  
  METHODS
  The rate and extent of serum thromboxane generation and aspirin pharmacokinetics were measured in 40 patients with diabetes in a randomized, single-blind, triple-crossover study. Patients were exposed to three 325-mg aspirin formulations: plain aspirin, PL2200 (a modified-release lipid-based aspirin), and a delayed-release enteric-coated (EC) aspirin. Onset of antiplatelet activity was determined by the rate and extent of inhibition of serum thromboxane B2(TXB2) generation. Aspirin nonresponsiveness was defined as a level of residual serum TXB2associated with elevated thrombotic risk (<99.0% inhibition or TXB2>3.1 ng/ml) within 72 h after 3 daily aspirin doses.
  
  
  RESULTS
  The rate of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200, and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin-treated subjects had serum TXB2levels >3.1 ng/ml, compared with 18% and 11% of subjects after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid (63% and 70% lower geometric mean maximum plasma concentration [Cmax] and 77% and 82% lower AUC0-t[area under the curve from time 0 to the last time measured]) and 66% and 72% lower maximum decrease of TXB2, with marked interindividual variability.
  
  
  CONCLUSIONS
  A high proportion of patients treated with EC aspirin failed to achieve complete inhibition of TXB2generation due to incomplete absorption. Reduced bioavailability may contribute to "aspirin resistance" in patients with diabetes. (Pharmacodynamic Evaluation of PL2200 Versus Enteric-Coated and Immediate Release Aspirin in Diabetic Patients; NCT01515657).
authors.affiliation: Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts. Electronic address: dlbhattmd@post.harvard.edu.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Tilo
authors.initials: T
authors.lastname: Grosser
authors.affiliation: Hematology Division, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Dong
authors.affiliation: Veterans Administration Medical Center, Cincinnati, Ohio.
authors.forename: Douglas
authors.initials: D
authors.lastname: Logan
authors.affiliation: Loyola University Chicago, Cardiovascular Research Institute, Maywood, Illinois.
authors.forename: Walter
authors.initials: W
authors.lastname: Jeske
authors.affiliation: University of Florida College of Medicine, Jacksonville, Florida.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
authors.affiliation: Harvard Clinical Research Institute, Boston, Massachusetts.
authors.forename: Lanyu
authors.initials: L
authors.lastname: Lei
authors.affiliation: Medpace Inc., Cincinnati, Ohio.
authors.forename: Juan
authors.initials: J
authors.lastname: Liang
authors.affiliation: PLx Pharma Inc., Houston, Texas.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Moore
authors.affiliation: University of Texas Southwestern and VA North Texas Health Care System, Dallas, Texas.
authors.forename: Byron
authors.initials: B
authors.lastname: Cryer
authors.affiliation: PLx Pharma Inc., Houston, Texas.
authors.forename: Upendra
authors.initials: U
authors.lastname: Marathi
mesh_terms: D000328:Adult; D001241:Aspirin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004304:Dosage Forms; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D004304:Dosage Forms; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; D001241:Aspirin
keywords: acetylsalicylic acid; enteric coating; pharmacodynamics; pharmacokinetics; platelet function; thromboxane