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Two-stage vs mixed-effect approach to pharmacodynamic modeling of propofol in children using state entropy
Jin-Oh Hahn1, Sara Khosravi, Guy A Dumont
1Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada. jinoh.hahn@alum.mit.edu
Insights
This study compared two methods for modeling propofol
Area of Science:
- Pharmacology
- Pharmacokinetics
- Pharmacodynamics
Background:
- Population pharmacodynamic (PD) models are crucial for understanding drug effects in diverse patient groups.
- Propofol is a widely used anesthetic agent, and accurate modeling is essential for safe and effective administration in pediatric populations.
- Comparing different modeling approaches helps refine analytical methods and improve clinical application.
Purpose of the Study:
- To compare population pharmacodynamic (PD) models of propofol in children using two-stage and mixed-effect modeling.
- To evaluate the prediction performance of these models.
Main Methods:
- Fifty-two children (6-15 years) received propofol infusions.
- Plasma concentrations were predicted using the Paedfusor pharmacokinetic (PK) model.
- Propofol's effect on state entropy (SE) was modeled using two-stage and mixed-effect approaches, comparing prediction errors.
Main Results:
- Both two-stage and mixed-effect models yielded comparable population PD parameters for propofol in children.
- Key parameters (k(e0), γ, EC(50)) were consistent between the two methods.
- Age and body weight were not significant covariates, and pediatric parameters differed from adult values.
Conclusions:
- Consistent propofol PD model parameters were achieved with both two-stage and mixed-effect modeling approaches.
- The two-stage approach offers computational efficiency and is a viable alternative to mixed-effect modeling for non-sparse data.
- These findings support the use of robust modeling techniques for pediatric propofol administration.
Objectives:
To compare the population pharmacodynamic (PD) models of propofol in children derived using two-stage and mixed-effect modeling approaches.
Methods:
Fifty-two ASA 1 and 2 children aged 6-15 years presenting for gastrointestinal endoscopy were administered a loading dose of 4 mg·kg(-1) of propofol intravenously at an infusion rate determined by a randomization schedule. Using the plasma concentration predicted by the Paedfusor pharmacokinetic (PK) model, the propofol effect on state entropy (SE) was modeled using the two-stage and the mixed-effect modeling approaches, and the final population PD models were compared with each other in terms of their prediction performance, using median percentage and absolute percentage errors as well as mean absolute weighted error as metrics. The effects of age and body weight as prospective covariates were examined.
Results:
The final population models were comparable with each other; the two-stage and the mixed-effect approaches resulted in a k(e0) of 2.38 and 2.66 min(-1), γ of 5.29 and 5.68, and EC(50) of 4.73 and 4.84 μg·ml(-1), respectively. The bootstrap estimates of the PD parameters were mean (SD) k(e0) = 2.38 (0.10), γ = 5.30 (0.30), and EC(50) = 4.73 (0.14). The PD parameters did not exhibit dependence on age and body weight. The parameters reported in this study in children were different from their adult counterparts reported in previous studies.
Conclusions:
Models derived using different mathematical approaches produced consistent model parameters. By virtue of its relative computational efficiency, the two-stage approach can serve as an attractive alternative to the mixed-effect approach in situations where data are not sparse.
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