Computer-controlled infusion of ORG 21465, a water soluble steroid i.v. anaesthetic agent, into human volunteers

ORG 21465 has been found to possess anaesthetic properties in humans and its pharmacokinetics are known. We performed this study to confirm the characteristics associated with its administration and to define its pharmacodynamic profile, in particular to explore the relationship between sedation, anaesthesia, excitation and plasma drug concentrations. A water soluble preparation of ORG 21465 was administered to six male volunteers as a series of three 15-min computer-controlled, pharmacokinetic model-driven infusions targeting three exponentially increasing plasma concentrations: 0.5, 1 and 2 μg ml^-1. The clinical characteristics of the resultant sedation and anaesthesia were observed. Plasma concentrations of ORG 21465 were measured during and for 500 min after the infusions and the EEG recorded. A sigmoid e-max effect compartment pharmacodynamic model was fitted to the plasma concentrations and an EEG derivative (spectral edge frequency (SEF)). Anaesthesia with ORG 21465 was associated with involuntary movements in all subjects. A steady state concentration of 1180 ng ml^-1 depressed SEF by 50%, the Hill factor describing the sigmoid nature of the concentration-response curve was 1.42 and the equilibration rate constant of the biophase was 0.112 min^-1. Anaesthesia with ORG 21465 was found to be unsatisfactory because of involuntary movements and slow equilibration with the biophase.