Glasgow Meeting - May 2003

The in vivo activity of THRX-918661, a novel, pharmacokinetically-responsive sedative/hypnotic agent.

D. Beattie, T. Jenkins, J. McCullough, H. Thibodeaux, T. Renner, J. Bolton, *D. Cook, *S. Steffensen, **T. Egan & ***S. Shafer, Theravance, Inc., South San Francisco, *NeuroInsight, LLC, **Department of Anesthesiology, University of Utah School of Medicine and ***Anesthesia Department, Stanford University School of Medicine.

The in vivo pharmacological activity of THRX-918661, a metabolically labile ester and positive allosteric modulator of the GABAA receptor, was evaluated. THRX-918661 produced hypnosis following bolus i.v. administration or infusion in rats, guinea-pigs, ferrets, cats, dogs and pigs, with a rapid onset of action. The primary metabolites of THRX-918661 were inactive in rats, following both bolus administration and infusion, at doses similar to, or in excess of those generated during THRX-918661 administration. An investigation of the effects of THRX-918661 on the rat EEG demonstrated that bolus i.v. administration (5-30mg/kg) produced a dose-dependent and short-lived suppression of the EEG, qualitatively similar in nature to that produced by Diprivan®, but with a more rapid recovery profile. The speed of recovery from hypnosis was unaffected by the duration of THRX-918661 infusion in rats, suggesting that the compound has a short and constant context-sensitive half-time. In contrast, recovery from Diprivan-induced anesthesia increased with the duration of the infusion. More rapid recovery for THRX-918661 (i.v. infusion of 1.5mg/kg/min for 20 mins), relative to Diprivan, was confirmed in pigs. Recovery of the bispectral index to pre-dose levels, occurred 5-10 minutes following termination of the infusion of THRX-918661, compared to 10-25 minutes for Diprivan. Experiments in rats demonstrated synergy between THRX-918661 and the opioids, fentanyl and remifentanil, to at least the same degree as that observed for Diprivan. In the presence of remifentanil, a 6-fold lower infusion dose of THRX-918661 (2.5mg/kg/min) maintained a surgical level of anesthesia in rats. Administration by bolus or infusion of THRX-918661 produced cardiovascular responses (hypotension and bradycardia) in rats and pigs, to a similar extent as those produced by Diprivan. The cardiovascular effects of THRX-918661, but not Diprivan, were rapidly reversed upon termination of infusion. While not pro-emetic in dogs and ferrets, THRX-918661, demonstrated no anti-emetic activity in ferrets. Thus, while Diprivan attenuated morphine-induced emesis, THRX-918661 had no such effect, presumably as a consequence of its rapid offset of action.

It is concluded that THRX-918661 is a sedative/hypnotic agent in vivo. Recovery from THRX-918661-induced hypnosis is more rapid and predictable than that following Diprivan. As such, THRX-918661 may have clinical potential as a novel sedative/hypnotic agent with a rapid and predictable recovery profile.

THRX-918661, a novel, pharmacokinetically-responsive sedative/hypnotic agent

T. Jenkins, D. Beattie, S. Jaw-Tsai, S. Amagasu, J. Halladay, S. Vanapalli, R. Kern, J.P. Shaw, *T. Egan & **S. Shafer, Theravance, Inc., South San Francisco, CA, *Department of Anesthesiology, University of Utah School of Medicine and **Anesthesia Department, Stanford University School of Medicine.

The offset of action of currently used sedative hypnotic agents (e.g. propofol) is mediated by redistribution kinetics. Identification of a clinically useful, metabolically labile sedative-hypnotic agent, is the focus of our efforts at Theravance, Inc. Such an agent is expected to have a short and constant context-sensitive half-life, resulting in rapid and predictable patient emergence, regardless of the duration of infusion or depth of anesthesia achieved. This type of approach in the analgesia field resulted in the identification of remifentanil, recovery from which is rapid and predictable following termination of its infusion, in contrast to that of other opioids (e.g. fentanyl) which rely on redistribution kinetics. THRX-918661 is a positive allosteric modulator of the GABAA receptor. Electrophysiological studies have demonstrated that THRX-918661 potentiates GABAA-mediated chloride currents in rat neocortical neurons (approximate pEC50 of 4.7 in comparison to 6.2 for propofol). THRX-918661 is a metabolically-labile ester. Its hydrolysis occurs rapidly in rat and guinea-pig whole blood (t1/2 values of 0.4 and 0.1 mins respectively) and in cat, dog and pig liver microsomes (t1/2 values of 2, 2 and <1 mins respectively). The t1/2 values for THRX-918661 in human whole blood and liver microsomes are 10 and 2 mins respectively. Metabolism of THRX-918661 in blood or liver microsomes results in the formation of the expected carboxylate metabolite, consistent with hydrolysis by esterases. In vitro data indicate that butyrylcholinesterase plays a more important role than acetylcholinesterase in the hydrolysis of THRX-918661. Following i.v. infusion in rats, THRX-918661 (6-8mg/kg/min for 3 hrs) is metabolized primarily to its inactive carboxylate metabolite. Blood concentrations of the parent ester are detectable for only 5 mins after terminating the infusion. Following i.v. infusion in pigs (1.5mg/kg/min for 20 mins), the clearance of THRX-918661 is considerably greater than that of propofol (3.2 vs. 2.0L/hr/kg respectively) and its t1/2 is shorter (0.5 and 1.8 hrs respectively). A radiolabeled study in the rat has indicated that following infusion of THRX-918661, the majority of the dose is eliminated via the kidneys. No tissue (i.e. blood, cerebrospinal fluid, brain, skeletal muscle, heart, lung, liver, spleen and brown fat) accumulation is evident 24 hours after initiation of a 3 hour infusion.

It is concluded that THRX-918661 is a rapidly metabolized, positive allosteric modulator of the GABAA receptor and as such may offer clinical potential as a pharmacokinetically-responsive sedative/hypnotic agent.