First In-Human Experience With Inhaled Acetylsalicylic Acid for Immediate Platelet Inhibition
2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 13 Linguagem: Inglês
10.1161/circulationaha.120.047477
ISSN1524-4539
AutoresPaul A. Gurbel, Kevin P. Bliden, Rahul Chaudhary, Udaya S. Tantry,
Tópico(s)Pharmacology and Obesity Treatment
ResumoHomeCirculationVol. 142, No. 13First In-Human Experience With Inhaled Acetylsalicylic Acid for Immediate Platelet Inhibition Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBFirst In-Human Experience With Inhaled Acetylsalicylic Acid for Immediate Platelet InhibitionComparison With Chewed and Swallowed Acetylsalicylic Acid Paul A. Gurbel, MD Kevin P. Bliden, MBA Rahul Chaudhary, MD Udaya S. TantryPhD Paul A. GurbelPaul A. Gurbel Paul A. Gurbel, MD, Director, Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Baltimore MD, 21215. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5461-568X Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T.). , Kevin P. BlidenKevin P. Bliden Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T.). , Rahul ChaudharyRahul Chaudhary Division of Hospital Internal Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN (R.C.). , Udaya S. TantryUdaya S. Tantry Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, MD (P.A.G., K.P.B., U.S.T.). Originally published28 Sep 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047477Circulation. 2020;142:1305–1307An initial loading dose of 162 to 325 mg non–enteric-coated acetylsalicylic acid (ASA) is recommended as first-line therapy in patients with myocardial infarction to provide rapid inhibition of platelet aggregation (PA).1 The anti-ischemic effects of ASA are primarily attributed to blockade of the platelet cyclooxygenaxe-1 enzyme and subsequent inhibition of thromboxane A2 (TxA2) generation and TxA2-induced PA.1 Arachidonic acid (AA)–induced PA and the inhibition of serum TxB2, the stable metabolite of TxA2, indicate the direct effect of aspirin in blocking platelet cyclooxygenaxe-1 and have been used as standard assays to assess the platelet inhibitory effect of ASA. Adenosine diphosphate (ADP)–induced PA is a direct measure of the response of the platelet to stimulation by ADP, which is a combined effect mediated by the P2Y1 and P2Y12 receptors.2 ADP stimulation also produces TxA2 through outside-in signaling and thus is a less direct marker of cyclooxygenaxe-1 activity.2 The time for 50% inhibition of serum TxB2 was 5 minutes after a chewed tablet versus 12 minutes when swallowed.3 An even more rapid pharmacodynamic effect would be desirable during the early phase of thrombus evolution in the setting of myocardial infarction or ischemic stroke.An inhaled nanoparticle ASA preparation, administered with a dry powder inhaler (Otitopic, Inc, Los Angeles, CA), was developed to enhance the speed of platelet inhibition induced by ASA. The inhaled ASA (I-ASA) formulation bypasses gastrointestinal and hepatic metabolism and has the potential to provide rapid drug exposure from the pulmonary circulation. The inhaler is small and similar in size to inhalers used to treat lung disease. We hypothesized that the pharmacodynamic and pharmacokinetic profiles of I-ASA are more rapid than with chewed and swallowed soluble ASA (C-ASA).In this pilot, phase 1, open-label, single dose–escalation study (Pharmacodynamics and Pharmacokinetics of Aspirin Inhalation Powder With Non-Enteric-Coated Chewable Aspirin; URL: https://www.clinicaltrials.gov; Unique identifier: NCT04328883), the pharmacodynamics and pharmacokinetics of I-ASA (50 mg [n=6] and 100 mg [n=5]) were compared with those of 162 mg C-ASA (n=6) in healthy adults with normal pulmonary function (forced expiratory volume in 1 second >80% of predicted value). The study was approved by the local institutional review committee, and the participants gave informed consent. We measured 1 mmol/L AA-induced PA, 4 µg/mL collagen-induced PA, and 5 µmol/L ADP-induced PA by conventional aggregometry; serum TxB2 (Eicosanoid Core Laboratory, Nashville, TN) and plasma ASA (NorthEast BioAnalytical Laboratories, Hamden, CT) concentrations by liquid chromatography–mass spectrometry; and urinary 11-dehydro-TxB2 (Inflammatory Markers Laboratory, Wichita, KS) by enzyme-linked immunoassay serially over a 24-hour period.4,5The effects of I-ASA and C-ASA on AA-induced PA and serum TxB2 are shown in the Figure A and B. Complete inhibition of AA-induced PA was achieved within 2 minutes with both I-ASA doses versus within 30 minutes with C-ASA. AA-induced PA after both 50 and 100 mg I-ASA remained lower than with C-ASA for the first 10 minutes (P<0.02). Inhibition of serum TxB2 was observed within 2 minutes in all groups (Figure B) but was greatest with 100 mg I-ASA. Inhibition of serum TxB2 remained greater in the 100 mg I-ASA versus the C-ASA group for the first 5 minutes. Maximal inhibition of serum TxB2 was sustained for 24 hours for all groups. ADP-induced final PA was lower within 2 minutes with 50 and 100 mg I-ASA and within 30 minutes with C-ASA compared with baseline (44±14% versus 64±9%, P=0.01; 40±14% versus 71±5%, P=0.0006; and 45±22% versus 67±8%, P=0.04, respectively). Collagen-induced final PA was lower within 2 minutes with 100 mg I-ASA and within 40 minutes with C-ASA as compared with baseline (63±11% versus 75±5%, P=0.02; and 45±22% versus 67±8%, P<0.05, respectively). Urinary 11-dehydro-TxB2, a marker of in vivo TxA2 generation, was measured at baseline and 4- and 24-hour postdosing. All groups had a significant reduction in urinary 11-dehydro-TxB2 levels (P<0.01 versus baseline at 4 hours).Download figureDownload PowerPointFigure. Pharmacodynamic effects of inhaled acetylsalicylic acid (I-ASA) and chewed and swallowed soluble acetylsalicylic acid (C-ASA).A, Arachidonic acid (AA)–induced platelet aggregation. *P<0.0001 vs baseline for both doses of I-ASA. **P<0.02 vs baseline for C-ASA. +P<0.0001 for both I-ASA groups versus C-ASA. ++P≤0.002 for both I-ASA groups vs C-ASA. B, Inhibition of serum thromboxane B2. *P≤0.0003 vs baseline for both doses of I-ASA. **P=0.01 vs baseline for C-ASA. +P=0.04 for 100 mg I-ASA vs C-ASA. ++P=0.07 for 100 mg I-ASA versus C-ASA.Maximum plasma concentration of ASA was greatest with 100 mg I-ASA (2894±788 ng/mL) as compared with 50 mg I-ASA (1370±724 ng/mL, P=0.009) and C-ASA (1896±669 ng/mL, P=0.05), and time to maximal concentration of ASA was shorter with 100 mg I-ASA (2 minutes) as compared with 50 mg I-ASA (4 minutes) and C-ASA (30 minutes). The area under the curve0–1 hour for 100 mg I-ASA and C-ASA did not differ (1055±141 and 1049±387 hours·ng/mL, P=not significant), whereas 50 mg I-ASA was lower (498±180 hours·ng/mL, P≤0.0003 for both). A pharmacokinetic/pharmacodynamic linear relationship was found between time to maximal concentration of ASA and time to antithrombotic effect indicated by inhibition of AA-induced PA (P<0.005 and r2=0.96).The results of our pilot study suggest that inhalation of ASA using a novel drug delivery device provides earlier greater drug exposure and is a faster pathway to achieve earlier greater platelet inhibition than the method of chewing and swallowing soluble ASA. These observations support further investigations of this novel aspirin delivery system designed to treat evolving arterial thrombus formation. Studies are being planned in consultation with the US Food and Drug Administration.Sources of FundingThis work was supported by Otitopic Inc.DisclosuresDr Gurbel reports grants and personal fees from Bayer HealthCare LLC and Otitopic Inc during the conduct of the study. He is a consultant for Otitopic Inc, the company producing nanoparticle aspirin. He also reports grants from Instrumentation Laboratory, grants from Haemonetics, grants and personal fees from Amgen, grants from Medicure Inc, grants and personal fees from Janssen, grants and personal fees from US WorldMeds LLC, grants from Idorsia Pharmaceuticals, personal fees from UpToDate, and grants from Hikari Dx outside the submitted work. Dr Gurbel has the following patents issued: Detection of restenosis risk in patients and Assessment of cardiac health and thrombotic risk in a patient. The other authors report no conflicts.Footnoteshttps://www.ahajournals.org/journal/circPaul A. Gurbel, MD, Director, Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Baltimore MD, 21215. Email [email protected]orgReferences1. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, Jaffe AS, Jneid H, Kelly RF, Kontos MC, et al.; ACC/AHA Task Force Members; Society for Cardiovascular Angiography and Interventions; and the Society of Thoracic Surgeons. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation. 2014; 130:2354–2394. doi: 10.1161/CIR.0000000000000133LinkGoogle Scholar2. Jin J, Quinton TM, Zhang J, Rittenhouse SE, Kunapuli SP. Adenosine diphosphate (ADP)-induced thromboxane A(2) generation in human platelets requires coordinated signaling through integrin alpha(IIb)beta(3) and ADP receptors.Blood. 2002; 99:193–198. doi: 10.1182/blood.v99.1.193CrossrefMedlineGoogle Scholar3. Feldman M, Cryer B. Aspirin absorption rates and platelet inhibition times with 325-mg buffered aspirin tablets (chewed or swallowed intact) and with buffered aspirin solution.Am J Cardiol. 1999; 84:404–409. doi: 10.1016/s0002-9149(99)00324-0CrossrefMedlineGoogle Scholar4. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study.Circulation. 2005; 111:1153–1159. doi: 10.1161/01.CIR.0000157138.02645.11LinkGoogle Scholar5. Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal NK, Gesheff T, Chaganti SK, Etherington A, Tantry US. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study.Circulation. 2007; 115:3156–3164. doi: 10.1161/CIRCULATIONAHA.106.675587LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 29, 2020Vol 142, Issue 13Article InformationMetrics Download: 2,794 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.047477PMID: 32986482 Originally publishedSeptember 28, 2020 Keywordsaspirinblood plateletsplatelet aggregationPDF download SubjectsClinical Studies
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