Pharmacokinetic/pharmacodynamic assessment of a novel, pharmaceutical lipid-aspirin complex: results of a randomized, crossover, bioequivalence study

Abstract

Aspirin (acetylsalicylic acid, ASA) can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer. A liquid formulation of a novel pharmaceutical lipid-aspirin complex (PL-ASA) was designed to prevent this disruption. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with immediate release aspirin (IR-ASA). In this active-control crossover study, 32 healthy volunteers were randomized to receive 1 of 2 dose levels (a single dose of 325 mg or 650 mg) of either PL-ASA or IR-ASA. After a 2-week washout period between treatment assignments, subjects received a single dose of the alternative treatment, at the same dose level. The primary objectives of the study were to assess, for PL-ASA and IR-ASA at 325 mg and 650 mg dose levels, PK and PD bioequivalence, and safety, over a 24-h period after administration of both drugs. PK parameters were similar for PL-ASA and IR-ASA, and met FDA-criteria for bioequivalence. Regarding PD, both drugs also showed Cmin TxB2 values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) and > 99% inhibition of serum TxB2 ( ≥ 95% inhibition represents the cut-off for aspirin responders) along with similar results in several secondary PK/PD parameters. There were no serious adverse events or changes from baseline in vital signs or laboratory values in either of the 2 treatment groups. PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA, supporting functional and clinical equivalence. These data coupled with the improved gastric safety of PL-ASA suggest that this novel formulation may exhibit an improved benefit-risk profile, warranting evaluation in future trials.Clinical trial registration: http://www.clinicaltrials.gov . Unique Identifier: NCT04008979.

Keywords: Aspirin; Bioequivalence; Pharmacodynamic; Pharmacokinetic; Platelet.

Conflict of interest statement

Dr Angiolillo declares that he has received consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has received payments for participation in review activities from CeloNova and St Jude Medical. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions. Dr. Deepak L. Bhatt discloses the following relationships—Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. Dr Cryer is a consultant for Horizon Pharma, PLx Pharma, and Ritter. Pharmaceuticals.Dr. Jeske is the principal investigator on a research grant to Loyola University Chicago from KinMaster Produtos Quimicos and has been a consultant to PLx Pharma Inc., Machaon Diagnostics, and Repros Therapeutics. Dr. Deliargyris, Mr, Zimmerman, and Ms, von Chong are employees of PLx Pharma. Dr. Prats is a consultant to PLx Pharma. Dr. Marathi was an employee of PLx Pharma at the time of the study, and is an investor, option holder, and a co-inventor of the PL-ASA delivery technology. All other authors report no conflicts related to the current study.

Figures

Fig. 1

Impact of the pharmaceutical formulation on aspirin’s disposition. Plasma concentration time profiles of acetylsalicylic acid (a, b) and salicylic acid (c, d) were compared in healthy, fasted volunteers who received single doses (325 and 650 mg) of PL-ASA and IR-ASA. h hours, IR-ASA immediate release aspirin, mg milligrams, ng nanograms, PL-ASA pharmaceutical lipid–aspirin complex

Fig. 2

Graphs of the mean concentration of TxB2. Decrease in TxB2 level from baseline was measured as a marker for inhibition of platelet aggregation by PL-ASA and IR-ASA (samples collected at baseline, and 2, 4, 6, 8, 10, and 24 h post-dose). Results are shown as mean % inhibition of TxB2 concentration for 325 mg (top panel) and 650 mg dose (bottom panel). h hours, IR-ASA immediate release aspirin, mg milligrams, mL milliliters, ng nanograms, PL-ASA pharmaceutical lipid–aspirin complex, TxB2 thromboxane B2

Fig. 3

Mean Percent Inhibition of Platelet Aggregation (IR-ASA and PL-ASA doses of 325 mg and 650 mg). The baseline levels of platelet aggregation induced by arachidonic acid and by collagen in platelet-rich plasma (PRP) prepared from blood samples collected at screening were determined. Platelet aggregation induced by each agonist was then measured in PRP prepared from blood drawn at 6 h and at 24 h after dosing, and the % inhibition of aggregation observed was calculated for each subject at each time point (compared to baseline). *P AA arachidonic acid, h hours, IR-ASA immediate release aspirin, PL-ASA pharmaceutical lipid–aspirin complex