Ekaterina Gibiansky (1), Michel MRF Struys (2), Leonid Gibiansky (3)
(1) Guilford Pharmaceuticals, Baltimore, MD, USA; (2) Dep. of Anesthesia, Ghent University Hospital, Gent, Belgium; (3) Emmes Corporation, Rockville, MD, USA
Background: Propofol is an intravenous sedative-hypnotic agent used for the induction and maintenance of general anesthesia, and sedation. AQUAVAN≥ Injection (GPI 15715) is a water-soluble prodrug of propofol. Preliminary investigation revealed that the PK and PK/PD of AQUAVAN≥ -derived propofol and propofol from the current lipid emulsion formulation are different. Our goal is to predict the pharmacodynamic effect of AQUAVAN≥ Injection over a wide range of doses (light sedation to induction of anesthesia).
Objectives: (1) To develop a predictive population PK/PD model of AQUAVAN≥-derived propofol.(2) To use the model for design of a Phase II, effect – controlled study of sedation during colonoscopy.
Methods: (1) A population PK model of Aquavan based on the rich data of 36 volunteers (single bolus doses 5-30 mg/kg) was used to predict individual propofol plasma concentrations. These predictions, coupled with the Bispectral Index (BIS, an EEG measure of sedation) data were used to establish the PK/PD model. The population PK and PK/PD models were combined into a simultaneous PK/PD model. Simulations, bootstrap, and leverage analyses were used for model evaluation.(2) In the planned study, AQUAVAN≥ Injection was to be administered as a bolus with supplemental doses administered if needed, based on the depth of sedation. The dosing regimen design was chosen based on study simulations, varying both initial and supplemental doses and the dosing interval. Model development and simulations were performed using NONMEM.
Results: (1)BIS change from baseline was described by a Hill function of propofol concentration in the effect compartment. The rate constant of the effect compartment was proportional to propofol plasma concentration. Neither weight nor gender affected the PK/PD relationship.(2) Clinical trial simulation predicted that an initial bolus of 10 mg/kg followed, if needed, by 5 mg/kg three minutes later, would provide an adequate sedation to 97% of patients. Of these patients, 50% would not require the supplemental dose to attain sedation.
Conclusions: A predictive population PK/PD model was developed over a wide range of doses. Doses pre-elected to produce the desired level of effect (light sedation to induction of anesthesia) were identified. The simulations confirmed the feasibility of using bolus doses of AQUAVAN≥ Injection to achieve and maintain sedation for short (20 √30 minutes) diagnostic and therapeutic procedures. The model-based clinical trial simulation was used to guide the dosing design of the sedation effect-controlled trial in patients.
Reference: PAGE 12 (2003) Abstr 413 [www.page-meeting.org/?abstract=413]
Poster: poster