Alphaxalone Anaesthesia PKPD

Background  Alphaxalone is an intravenous anaesthetic that has been formulated for human use as Phaxan™, an aqueous solution of alphaxalone 10 mg mL-1 and 13% betadex.  This study assessed the pharmacokinetic-pharmacodynamic (PKPD) characteristics of alphaxalone (Phaxan™) in humans.

Methods: Alphaxalone 0.5 (0.42-0.55) [mean (range); mg kg-1] was given by single intravenous bolus injection of Phaxan™ to 12 healthy subjects. Plasma alphaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated PKPD model using non-linear mixed effects models. Allometry, scaled to a 70-kg person, was used for PK size standardisation. Effect (BIS) was described using a factional sigmoidal EMAX model.

Results:  A 3-compartment model to fit PK data with an additional compartment, linked by an equilibration half-time (t1/2keo) to describe the effect compartment, yielded Phaxan™ alphaxalone PK parameter estimates: clearance (CL) 1.11 L min-1; central volume of distribution (V1) 1.06 L; inter-compartment clearance (Q2) 0.43 L min-1; peripheral volume of distribution (V2) 20.7 L;  inter-compartment clearance (Q3) 0.893 L min-1; and peripheral volume of distribution (V3) 6.44 L. PD interrogation revealed a baseline BIS of 90.7, a fractional maximum effect (EMAX) 0.94, a C50 of 0.98 mg L-1, and a Hill coefficient (γ) 12.1. The t1/2keo was 8.2 minutes. The mean time to a BIS 50 was 0.73 (SD 0.19) min.

Conclusions:  Phaxan™ has similar clearance but reduced volume of distribution compared with Althesin.  The t1/2keo is greater than that reported for propofol (t1/2keo 3 min) but the large Hill coefficient contributes to rapid onset of action.