AQUAVAN® injection, a water-soluble prodrug of propofol, as a bolus injection: A phase I dose-escalation comparison with DIPRIVAN® (part 1) - Pharmacokinetics

Abstract

Background: AQUAVAN® Injection (AQ) (GPI 15715; Guilford Pharmaceutical Inc., Baltimore, MD) is a water-soluble prodrug of propofol (Propofol GPI). This study aimed to explore the pharmacokinetics of AQ, Propofol GPI, and formate (a metabolite of AQ) and to compare them with the pharmacokinetics of propofol lipid emulsion (Propofol D). Methods: After ethics committee approval, 36 healthy volunteers were randomly allocated into six cohorts (male/female: 3/3) and given a single bolus of AQ (5, 10, 15, 20, 25, or 30 mg/kg). For comparison, an equipotent dose (as measured by the Bispectral Index) of Propofol D was given to the same subjects 1 week later. For both drugs, blood samples were collected (1-480 min) to analyze AQ, Prpofol GPI, Propofol D, and formate concentrations. Noncompartmental pharmacokinetic analyses were performed for all analytes. A population compartmental model was developed for AQ and Fropofol GPI using NONMEM. The models were evaluated using simulations and bootstraps. Results: The noncompartmental pharmacokinetic comparison revealed different dispositions of Propofol GPI and Propofol D. The maximum plasma concentration was lower for Propofol GPI than for Propofol GPI at equipotent doses, and apparent clearance and distribution volume were much higher for Propofol GPI than for Propofol D. Formate concentrations were similar when injecting both drugs and were not higher than baseline. Compartmental modeling revealed that the pharmacokinetic behavior of AQ and its liberated Propofol GPI was best described by a nonlinear, six-compartment model, composed of two three-compartment models connected to each other by hydrolysis of AQ to Propofol GPI. Conclusions: Propofol GPI showed different noncompartmental pharmacokinetics from Propofol D, hereby revealing the influence of the formulation. The combined model for AQ and Propofolo GPI was best modeled by a nonlinear, six-compartment model. © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.