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A4002
October 14, 2014
8:00 AM - 9:30 AM
Room Room 245
Phase 1c Trial Comparing the Anaesthetic Properties of Phaxan™ and Propofol
Colin S. Goodchild, M.A., M.B., BChir, Ph.D., F.R.C.A FANZCA FFPMANZCA, John Monagle, M.B., B.S., F.A.N.Z.C.A., Lyndon Siu, M.B.B.S., F.A.N.Z.C.A., Jodie Worrell, R.N., Juliet M. Serrao, M.B.B.S., Ph.D., F.R.C.A.
Monash Institute of Medical Research, Malvern, Victoria, Australia
Introduction:

Alphaxalone is a neuroactive steroid anesthetic. This water-insoluble drug, formulated as Althesin using CremophorEL to dissolve it, was an intravenous anesthetic used widely in clinical practice from 1972-1984a. Althesin was withdrawn from the market because of hypersensitivity to the CremophorEL. Phaxan is an aqueous solution of alphaxalone 10mg/ml and 13% 7-sulfobutylether beta-cyclodextrin [betadex; Dexolve]; a molecule with a lipophilic cavity that enables drug dispersal in water for human use. In preclinical studies Phaxan is as fast onset and offset intravenous anaesthetic as propofol with less effect on blood pressure (BP) and a therapeutic index (TI) greater than 30 (TI of propofol is 6). The aims of this first in human study were to find the dose of Phaxan that caused anaesthesia and to compare it with propofol for speed of onset and recovery, cardiovascular and respiratory effects and side effects such as involuntary movements, nausea, and pain on injection.

Methods:

The study was IRB approved, registered with the Therapeutic Goods Administration, and listed on a clinical trials registry (ACTRN12611000343909). The trial design was randomised, double blind, comparing propofol and Phaxan using a Bayesian algorithm to determine dose equivalence for effects on the bispectral index (BIS). 24 male volunteers ASA grade 1 gave written informed consent (n=12 per group; propofol, Phaxan). Parameters assessed for 90 minutes after drug injection (single bolus dose) were: BP, BIS, oxygen saturation, need for airway and ventilatory support, pain on injection, involuntary movement, nausea, and measures of recovery - the Richmond Agitation and Sedation Scale (RASS) and the Digital Symbol Substitution Test (DSST).

Results:

The Phaxan solution was clear and water-like. No subject complained of pain on injection with Phaxan whereas 8 of 12 subjects given propofol did (p=0.0013; Fisher's exact test). Involuntary muscle movement occurred only in the propofol treated group (3 of 12). Eleven subjects in each group were anaesthetised to a BIS value of 50 or less: propofol dose 2.31 (3.00-1.76; median, 75% IQ) mg/kg; Phaxan 0.49 (0.55-0.46; median, 75% IQ) mg/kg. The lowest average BIS reached was 28 for both propofol and Phaxan treated subjects with no difference between treatments for timing of fall and recovery of BIS. Nine subjects in each group received doses of drug that were within the IQ range. These were compared as shown in table 1.

Table

Figure

Conclusions:

Alphaxalone 10mg/ml in aqueous solution with 13% 7-sulfobutyl ether beta cyclodextrin (Phaxan) causes fast onset short duration anaesthesia equivalent to propofol but with less cardiovascular and respiratory depression and no pain on injection. The induction dose and duration of anaesthesia with Phaxan is the same as that reported previously for alphaxalone formulated as Althesinb. Therefore Phaxan can be expected to be an alternative to propofol for anaesthesia, sedation and ICU practice; safer in use and without lipid.

References:

a.

Prys-Roberts C, Sear J. Steroid Anaesthesia. Br J Anaesth 1980; 52(4):363-5

b.

Clarke RS, Dundee JW, and Carson IW. A new steroid anaesthetic-Althesin. Proc R Soc Med. 1973; 66(10): 1027-30.
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