Leonid Gibiansky (1), Michel MRF Struys (2), Ekaterina Gibiansky (3)
(1) Emmes Corporation, Rockville, MD, USA; (2) Dep. of Anesthesia, Ghent University Hospital, Gent, Belgium; (3) Guilford Pharmaceuticals, Baltimore, MD, USA
Background: Propofol, an intravenous anesthetic agent, is used for the induction and maintenance of general anesthesia and sedation. Infusion of propofol emulsion results in rapid onset and offset of anesthesia, which makes it a widely used agent. AQUAVAN™ (GPI 15715), a water-soluble prodrug of propofol, eliminates the emulsion related disadvantages of the current propofol formulation. In addition, AQUAVAN™ provides a more gradual onset and offset of action, which is beneficial in some settings; e.g., short-term sedation where it may be administered as an injection. Preliminary investigations revealed a non- linearity of AQUAVAN™ -derived propofol pharmacokinetics; therefore, it is vitally important to develop a PK model that can be used to optimize dosing and predict results of future studies.
Objectives: To develop a population PK model of AQUAVAN™ and AQUAVAN™- derived propofol over a wide range of doses (from light sedation to induction of anesthesia) .
Methods: Arterial plasma samples from a dose ranging study (5 to 30 mg/kg) of AQUAVAN™ administered as a bolus to 36 healthy volunteers were collected and analyzed. Rich plasma concentration/time data in the interval from 1 to 480 minutes post dose were available for both AQUAVAN™ and AQUAVAN™ -derived propofol. The simultaneous population PK analysis was performed using NONMEM. The influence of weight and gender on exposure was examined. Bootstrap and leverage analyses were used for model evaluation.
Results: AQUAVAN™-derived propofol pharmacokinetics was described by a nonlinear six-compartment model. AQUAVAN™ elimination was described by linear elimination and nonlinear metabolism to propofol. The rate of metabolism increased with AQUAVAN™ concentration, possibly due to saturation of protein binding. Propofol pharmacokinetics was described by linear elimination and saturable distribution. Weight influenced kinetics so that slightly less than weight-proportional dosing provided weight-independent exposure.
Conclusions: A predictive population PK model of AQUAVAN™-derived propofol was developed for a wide range of doses. The model suggested an explanation for the unique pharmacological profile of Aquavan administered as a bolus: rapid initial rate of metabolism slowing with falling Aquavan concentrations provides rapid onset of action and gradual offset. The model confirmed the adequacy of weight-adjusted dosing, and the absence of gender influence on AQUAVAN™-derived propofol exposure. The model was used for PK/PD modeling and for guiding dosing paradigm in a Phase II study.
Reference: PAGE 12 () Abstr 412 [www.page-meeting.org/?abstract=412]
Poster: poster