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A Population Pharmacokinetic Model of Pentobarbital for Children with Status Epilepticus and Severe Traumatic Brain
Naomi Ketharanathan1, Anastasia Lili2, Julia M Penning de Vries3
1Department of Neonatal and Paediatric Intensive Care, Division of Paediatric Intensive Care, Erasmus MC-Sophia Children's Hospital, Room Sp-3435, Wytemaweg 80, 3015GD, Rotterdam, The Netherlands. n.ketharanathan@erasmusmc.nl.
Insights
Pentobarbital dosing for critically ill children needs adjustment. Elevated creatinine and CRP levels decrease drug clearance, increasing toxicity risk. New dosing advice is provided for these patients.
Area of Science:
- Pharmacokinetics
- Pediatric Critical Care
- Pharmacometrics
Background:
- Pentobarbital pharmacokinetics (PK) are poorly understood, with narrow therapeutic windows.
- It is frequently used in pediatric intensive care units (PICU) for refractory status epilepticus (SE) and severe traumatic brain injury (sTBI).
Purpose of the Study:
- To develop a population pharmacokinetic (PopPK) model for pentobarbital in critically ill children.
- To simulate dosing regimens to optimize pentobarbital therapy in this population.
Main Methods:
- A one-compartment PopPK model was developed using NONMEM® with retrospective data (n=36).
- Allometric scaling of weight was applied to clearance (CL) and volume of distribution (Vd).
- External validation and dosing simulations were performed.
Main Results:
- The model demonstrated that elevated creatinine and C-reactive protein (CRP) significantly correlated with decreased pentobarbital CL, explaining 84% of variability.
- Simulations indicated that patients with elevated creatinine and CRP may not reach therapeutic steady-state concentrations and risk toxicity with current dosing.
- External validation confirmed the model's predictive performance.
Conclusions:
- A PopPK model for intravenous pentobarbital was established, identifying creatinine and CRP as key factors influencing pentobarbital CL.
- Adjusted dosing recommendations were formulated for patients with elevated creatinine and/or CRP.
- Prospective studies are crucial to optimize pentobarbital dosing for safety and efficacy in critically ill children.
Background:
Pentobarbital pharmacokinetics (PK) remain elusive and the therapeutic windows narrow. Administration is frequent in critically ill children with refractory status epilepticus (SE) and severe traumatic brain injury (sTBI).
Objectives:
To investigate pentobarbital PK in SE and sTBI patients admitted to the paediatric intensive care unit (PICU) with population-based PK (PopPK) modelling and dosing simulations.
Methods:
Develop a PopPK model with non-linear mixed-effects modelling (NONMEM®) with retrospective data (n = 36; median age 1.3 years; median weight 10 kg; 178 blood samples) treated with continuous intravenous pentobarbital. An independent dataset was used for external validation (n = 9). Dosing simulations with the validated model evaluated dosing regimens.
Results:
A one-compartment PK model with allometrically scaled weight on clearance (CL; 0.75) and volume of distribution (Vd; 1) captured data well. Typical CL and Vd values were 3.59 L/70 kg/h and 142 L/70 kg, respectively. Elevated creatinine and C-reactive protein (CRP) levels significantly correlated to decreased CL, explaining 84% of inter-patient variability, and were incorporated in the final model. External validation using stratified visual predictive checks showed good results. Simulations demonstrated patients with elevated serum creatinine and CRP failed to achieve steady state yet progressed to toxic levels with current dosing regimens.
Conclusions:
The one-compartment PK model of intravenous pentobarbital described data well whereby serum creatinine and CRP significantly correlated with pentobarbital CL. Dosing simulations formulated adjusted dosing advice in patients with elevated creatinine and/or CRP. Prospective PK studies with pharmacodynamic endpoints, are imperative to optimise pentobarbital dosing in terms of safety and clinical efficacy in critically ill children.
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