Abstract
Purpose
This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes..
Methods
This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo.
Results
Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated.
Conclusions
Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.
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References
Fontana P, Alberts P, Sakariassen KS, Bounameaux H, Meyer J-P, Sorensen SA (2011) The dual thromboxane receptor antagonist and thromboxane synthase inhibitor EV-077 is a more potent inhibitor of platelet function than aspirin. J Thromb Haemost 9:2109–2111
Sakariassen KS, Alberts P, Fontana P, Mann J, Bounameaux H, Sorensen AS (2009) Effect of pharmaceutical interventions targeting thromboxane receptors and thromboxane synthase in cardiovascular and renal diseases. Future Cardiol 5:479–493
Moncada S, Vane JR (1978) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 30:293–331
Sakariassen KS, Femia E, Rothlin RP, Podda G-M, Razzari C, Pugliano M-T, Daray FM, Errasti EA, Armesto AR, Nowak W, Alberts P, Hermosilla R, Meyer J-P, Cattaneo M, Sorensen SA (2011) EV-077-3201-2TBS, a TP antagonist and TS inhibitor, reduces platelet aggregation in whole blood of type 2 diabetics with coronary artery disease on chronic aspirin therapy. J Thromb Haemost 9(Suppl. 2):Abstract O-MO-023
Sakariassen KS, Muggli R, Baumgartner HR (1989) Measurements of platelet interaction with components of the vessel wall in flowing blood. Methods Enzymol 169:37–70
Cattaneo M, Hayward CP, Moffat KA, Pugliano MT, Liu Y, Michelson AD (2009) Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the platelet physiology subcommittee of the SSC of the ISTH. J Thromb Haemost 7:1029
Sonksen JR, Kong KL, Holder R (1999) Magnitude and time course of impaired primary haemostasis after stopping chronic low and medium dose aspirin in healthy volunteers. Br J Anaesth 82:360–365
Wilhite DB, Comerota AJ, Schmieder FA, Throm RC, Gaughan JP, Rao AK (2003) Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time. J Vasc Surg 38:710–713
Cohen RA, Feletou M, Vanhoutte PM, Verbeuren TJ (2010) TP receptors and oxidative stress hand in hand from endothelial dysfunction to atherosclerosis. Adv Pharmacol 60:85–106
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695
Pratico D (2008) Prostanoid and isoprostanoid pathways in atherogenesis. Atherosclerosis 201:8–16
Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126
Santilli F, Mucci L, Davi G (2011) TP receptor activation and inhibition in atherothrombosis: the paradigm of diabetes mellitus. Intern Emerg Med 6:203–212
Vezza R, Mezzasoma AM, Venditti G, Gresele P (2002) Prostaglandin endoperoxides and thromboxane A2 activate the same receptor isoforms in human platelets. Thromb Haemost 87:114–121
Acknowledgements
Drs. Graham D. Allen, Norbert Bender, Joan Devine, Ricardo Hermosilla, Jessica Mann, and Klaus Kutz are thanked for critical review of the manuscript.
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Clinical trial registry and registration number of the trial: EudraCT Number: 2008-005984-32
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Richardson, A., Sakariassen, K.S., Meyer, JP. et al. Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation. Eur J Clin Pharmacol 69, 459–465 (2013). https://doi.org/10.1007/s00228-012-1348-9
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DOI: https://doi.org/10.1007/s00228-012-1348-9