Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep

Abstract

BackgroundCNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. MethodsThe stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg−1 (2 min infusion) of CNS 7056 in alternating order on separate days. ResultsCNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min−1 and a terminal half-life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min−1, and inter-compartmental clearances of 2.85 and 1.44 litre min−1, while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t1/2,ke0 for sedation was 1.78 min, and the EC50 was 0.10 µg ml−1. ConclusionsCNS 7056 has PK–PD properties compatible with its potential human use as a short-acting i.v. sedative.