P.McCormack, L. Aarons, N.Yeates, M. Nassim, J. Gardner and M. Russell
Introduction: AR-C69931MX is a potent and selective P2T receptor antagonist acting as an inhibitor of adenosine diphosphate (ADP) induced platelet aggregation which is in development for the treatment of arterial thrombosis.
Methods: 28 healthy male and female volunteers each received 4 ascending iv infusions ofAR-C69931MX at rates between 25 – 4000 ng min-1kg-1. The first 3 doses were administered over 1 hour with the last infused over 20 hours. Plasma concentrations of both parent (AR-C69931XX) and the primary metabolite (AR-C69712XX) were analysed using NONMEM, and assessments made of platelet aggregation (whole blood) using in-vitro resistance measures (after a sub-maximal dose of ADP). Lancet bleed times were recorded during and after dosing.
Results: The pharmacokinetics (PK) of AR-C69931XX were described by a 2 compartment model with low intra (37 %) and inter-individual (23 %) variability. Plasma clearance (52 L h-1) had a low inter-individual variability (17 %) and no gender related differences were noted. The AR-C69931XX profiles were characterised by very rapid attainment of steady state (T1/2 = 3 mins) due to the high clearance and low initial volume of distribution (3 L). The pharmacodynamic effect of AR- C69931XX was such that the maximum reduction in the response was achieved at low concentrations (IC50= 9.9 ng mL-1). There was little clear evidence for effect on bleed time up to plasma concentrations of 500 ng mL-1. Bayesian parameter estimates of AR-C69931XX were used in the analysis of the AR-C69712XX data through a two compartment system.
Conclusion : AR-C69931MX is a compound with high plasma clearance and very short half-life enabling rapid attainment of steady state concentrations. It is effective in the suppression of ADP induced platelet aggregation and has little effect on bleed time at rates up to 4000 ng min-1kg-1. These preliminary findings support the development of this mechanistic route in the treatment of arterial thrombosis.
Acknowledgements : The staff of Inveresk and Medeval U.K and Rachel Blackshaw and Nicola Chesters, Astra Charnwood..
Reference: PAGE 7 (1998) Abstr 686 [www.page-meeting.org/?abstract=686]
Poster: poster