MDCO-700, a New Generation Anesthetic: Evaluation of Two Formulations in Sprague-Dawley Rats

Abstract

Background: MDCO-700(cyclopropyl-methoxycarbonyl metomidate) is a novel, potent, positive allosteric modulator of the γ-Aminobutyric Acid type A (GABAA) receptor currently being developed for general anesthesia and procedural sedation. Early studies were conducted with a formulation that had to be stored at frozen conditions. A new formulation was developed to enable storage under refrigerated conditions. The original formulation (MDCO-700-F1) and the new formulation (MDCO-700-F2) were both prepared in Sulfobutyl ether-β-cyclodextrin (Sbeβcd), however MDCO-700-F2 was prepared at a lower concentration and higher pH in order to improve long-term storage stability. The objective of this study was to compare the anesthetic effects of both formulations in male Sprague-Dawley rats. Methods: Rats received doses of either MDCO-700-F1 or MDCO700-F2 ranging from1 to 6 mg/kg. Doses were administered as an intravenous bolus over 5 seconds via surgically implanted jugular vein cannulas. Immediately after the bolus, rats were turned supine and the clinical signs of anesthesia were monitored until they returned to normal behavior. The relationships between dose and the anesthetic effects of MDCO-700 were analyzed and modeledusing pharmacodynamic models. Results: Both formulations rapidly produced similar dosedependent depths of sedation with increasing effect at higher doses. The time required for recovery, as assessed using qualitative and semi-quantitative metrics, increased with increasing dose and was similar for the two formulations. The dose-response for all measured parameters including arousal level, duration of action and full recovery were similar for both formulations. Conclusion: nder the conditions of this study, the data demonstrates that both formulations of MDCO-700 produced equivalent anesthetic effects in rats across the concentration range tested. These results suggest that either formulation can be used for ongoing clinical development.