Annual Scientific Meeting - 2001

Target Controlled Infusion of ORG25435, a New Intravenous Anesthetic Agent

J. Robert Sneyd, T. Tsubokawa, Maurice Cross, John Lytle, Chris Andrews, David Lunn, John Curnow, Patrick Boen, Rob Van Maanen, Leon Visser, Natalie S. Houwing and Peter C.M. Vijn. Anaesthesia Dept., Derriford Hospital, Plymouth, Devon, United Kingdom.

Corresponding Author: J. Robert Sneyd MD Department/Institution: Peninsula Medical School

Address: ITTC Building, Tamar Science Park, Davy Road, Plymouth PL6 8BX, UK. Phone: +44 1752 764221 Fax: +44 1752 764226 E-Mail: robert.sneyd@pms.ac.uk

Introduction Following preliminary animal experiments and appropriate toxicology, we have evaluated in man the safety and efficacy of ORG25435, a novel water-soluble anesthetic.

Method Seven male subjects aged 31.6±3.4yr (mean±SD) weighing 78.9±6.0kg received a 30 minute Target Controlled Infusion (TCI) of ORG25435. STANPUMP software using a preliminary pharmacokinetic model derived from 1 minute infusions into man of  ORG25435 (1). Initial TCI target plasma concentration was 5mcg ml^-1. If stable anesthesia was observed in the 0-15 minute infusion interval, the TCI target during the 15-30 minute infusion interval was not changed, otherwise it was increased by 50%. Each subsequent subject was started at the highest TCI target used in the previous subject. Once stable anesthesia was identified in two subjects over the complete period of 30 minutes, the remaining subjects were studied at TCI targets  up to 1.5 times greater. In addition to standard anesthetic monitoring, we recorded direct arterial blood pressure, EEG, trans-thoracic impedance cardiac output and video images. Appropriate arterial and venous blood samples were collected for pharmacokinetic analysis and biochemical and hematological safety data.

Results Consecutive subjects received ORG25435 5.8, 8.9, 12.9, 12.7, 14.8, 20.0 and 20.0mg kg^-1. Two  subjects became sedated and five lost consciousness in 1.5 (0.8-3.1)min, mean (range). The modest excitatory phenomena seen during short infusions (1), appeared more often and to a greater magnitude during TCI. Blood pressure was stable and heart rate increased at higher doses. Mean recovery time from end of anesthesia to eye opening on command was 5.4 min. Using NONMEM, a weight-normalized three-compartment pharmacokinetic model with the fast distributional clearance affected by the dose administered per unit time was developed from these subjects and 18 previously studied (1). Estimated parameters, typical value (SE): clearance, 7.94 (0.528)ml.kg^-1.min^-1; Q₂, 28.2 (4.13)ml.kg^-1.min^-1 unless ³3 mg.kg^-1 given over 1 min when Q₂ =128 (30.0); Q₃, 14.3 (2.26)ml.kg^-1.min^-1; V₁, 80.3 (10.7); V₂,  466 (41.9); V₃ 1290 (64.0)ml.kg^-1.

Conclusion ORG25435 is an effective IV anesthetic in man.  Excitation and  tachycardia make it unsuitable for further clinical development.

Reference

1. Sneyd, JR, Tsubokawa1, T, Andrews, CJH, Curnow, J, Cross, M, Lytle, J, Visser, V, Lunn, DV, Houwing, NS, Boen, P, van Maanen, R, Vijn, PCM. 2001. First administration to man of Org25435, a new intravenous anaesthetic agent. British Journal of Anaesthesia, 86 323P.

Financial Disclosure: Professor Sneyd is a paid consultant to Organon Teknika
Certain authors are employees of a related company (Organon).
Supported by: Organon Teknika