First In-Human Experience With Inhaled Acetylsalicylic Acid for Immediate Platelet Inhibition

aspirin ◼ blood platelets ◼ platelet aggregation A n 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 A 2 (TxA 2 ) generation and TxA 2 -induced PA. 1 Arachidonic acid (AA)-induced PA and the inhibition of serum TxB 2 , the stable metabolite of TxA 2 , 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 P2Y 1 and P2Y 12 receptors.2 ADP stimulation also produces TxA 2 through outside-in signaling and thus is a less direct marker of cyclooxygenaxe-1 activity.2 The time for 50% inhibition of serum TxB 2 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 TxB 2 (Eicosanoid Core Laboratory, Nashville, TN) and plasma ASA (NorthEast BioAnalytical Laboratories, Hamden, CT) concentrations by liquid chromatography-mass spectrometry; and urinary 11-dehydro-TxB 2 (Inflammatory Markers Laboratory, Wichita, KS) by enzyme-linked immunoassay serially over a 24-hour period.4,5 The effects of I-ASA and C-ASA on AA-induced PA and serum TxB 2 are shown in the Figure A and B. Complete inhibition of AA-induced PA was achieved