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Background <p>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.</p> Methods <p>Beagles receiving a single intravenous infusion of fospropofol at varying doses were divided into three groups (<i>n</i> = 6): the DBL-fospro group (15&#xa0;mg/kg), the DBM-fospro group (30&#xa0;mg/kg), and the DBH-fospro group (60&#xa0;mg/kg). Propofol levels were monitored using VUV-TOF MS from pre-administration to recovery. Correlations between Ce-pro-f and blood concentration (C<sub>blood</sub>-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.</p> Results <p>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<sub>blood</sub>-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<sub>blood</sub>-pro. The PD component was well fitted by the inhibitory sigmoid E<sub>max</sub> model, with an indirect connection model selected to explain the observed lag between BIS signals and Ce-pro-f peaks.</p> Conclusions <p>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 E<sub>max</sub> model with an indirect connection model to capture the lag between BIS and exhaled propofol peaks.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年2月28日

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  • Xiaoxiao Li,
  • Pan Chang,
  • Xing Liu,
  • Yi Kang,
  • Zhongjun Zhao,
  • Yixiang Duan,
  • Wensheng Zhang

摘要

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 (Cblood-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 Cblood-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 Cblood-pro. The PD component was well fitted by the inhibitory sigmoid Emax model, 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 Emax model with an indirect connection model to capture the lag between BIS and exhaled propofol peaks.