Pharmacokinetics & Anaesthetic Effects of Propofol-PM: A Novel Water Soluble Propofol Formulation

A E Rigby-Jones¹, J R Sneyd¹, F Ravenelle², P Vachon², D Le Garrec², S Gori², D Lessard², D C Smith²

1 Peninsula Medical School, Plymouth, UK  2 Labopharm Inc., Québec, Canada

Introduction

We have investigated the use of amphiphilic diblock copolymers of poly (N-vinyl-2-pyrrolidone) and poly-(D,L-lactide), PVP-PLA, to dissolve propofol inside micelles (30-60nm)¹.  We compared the pharmacokinetics (PK) of propofol in blood and plasma when administered as 1% Diprivan and as three 1% solutions reconstituted from Propofol-PM 7, 10 and 12% respectively. We also undertook a preliminary pharmacodynamic (PD) study. 

Methods

Forty male Sprague-Dawley rats (325±10g) were randomly allocated to one of 8 groups (5 rats/group). Ten rats were used for each of the 4 propofol formulations: 5 rats for the collection of blood samples and 5 for plasma samples. The rats were anaesthetised with isoflurane and both jugular veins exposed. Isoflurane was then discontinued.  When the animals responded to a hind paw pinch, they received propofol 10mg/kg (1 ml/kg over 1 min) via the jugular vein.  Blood samples were collected at 1, 3, 5, 7.5, 10, 15, 30, 60 and 75 min after injection.  A population PK model was constructed using NONMEM software.   Animal body weight, sample matrix (blood or plasma) and propofol formulation (Diprivan, Propofol-PM 7, 10 and 12%) were evaluated as model covariates. In a separate small PD study, the times of the recovery endpoints (leg withdrawal, first movement, righting) were compared for the four propofol formulations.

Results

The optimal PK model had two compartments and incorporated sample matrix and propofol formulation as dichotomous covariates.  Sample matrix was applied to all structural parameters.  An influence of propofol formulation was observed for all structural model parameters (excluding distributional clearance) but only when plasma was used as the sample matrix.  The effect of formulation was not apparent when whole blood concentrations of propofol were measured.   The figure below shows the average model predicted profiles.

There was no statistically significant difference in any of the recovery endpoints observed after administration of the four propofol solutions.

Discussion

The whole blood PK of Propofol-PM did not differ from that observed with Diprivan.  We observed lower propofol concentrations in plasma samples after Propofol-PM administration than after Diprivan but the quantity of the copolymer in the Propofol-PM formulations did not influence the PK.  Although there was no statistically significant difference in any of the recovery endpoints, the number of animals in the PD study was small (n=4-6 per formulation) and there was a high degree of variability.  Hence, the PD study was likely underpowered to detect small differences and must be regarded as preliminary.

References

1 F. Ravenelle, S. Gori, D. Le Garrec et al.  Pharmaceutical Research In Press