Developing a PK-PD model for propofol in exhaled air and the BIS following fospropofol disodium in beagles.

Abstract

BACKGROUND: Fospropofol, a water-soluble prodrug of propofol, is metabolized into propofol by alkaline phosphatase after administration. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model that correlates the propofol concentration in exhaled air (Ce-pro-f) with its anesthetic effects, as measured by the bispectral index (BIS) in beagles. METHODS: Beagles receiving a single intravenous infusion of fospropofol at varying doses were divided into three groups (n = 6): the DBL-fospro group (15 mg/kg), the DBM-fospro group (30 mg/kg), and the DBH-fospro group (60 mg/kg). Propofol levels were monitored using VUV-TOF MS from pre-administration to recovery. Correlations between Ce-pro-f and blood concentration (C-pro), as well as between Ce-pro-f and the BIS were investigated. PK, PD, and PK-PD models describing the relationship between Ce and BIS were also analyzed. RESULTS: Propofol concentration in exhaled air can be quantified using VUV-TOF MS at a mass-to-charge ratio of 177.6. After fospropofol injection, the peak Ce-pro-f was delayed compared to C-pro. The PK model of Ce-pro-f can be described using a noncompartmental approach, corresponding to the linear PK characteristics. Additionally, Ce-pro-f showed a moderate to strong negative correlation with BIS values. In the PK-PD model, the PK component was well characterized by a two-compartment model incorporating a first-order delay to account for the time lag of Ce-pro-f relative to C-pro. The PD component was well fitted by the inhibitory sigmoid Emodel, with an indirect connection model selected to explain the observed lag between BIS signals and Ce-pro-f peaks. CONCLUSIONS: This study is the first to develop a PK-PD model for exhaled propofol in beagles after fospropofol disodium administration. The PK profile was described by a two-compartment model with a first-order delay, and the PD profile was modeled using an inhibitory sigmoid Emodel with an indirect connection model to capture the lag between BIS and exhaled propofol peaks.