Physiologically-Based Pharmacokinetic Modeling of Total and Unbound Valproic Acid to Evaluate Dosing in Children With and Without Hypoalbuminemia.

Autor: Karatza E; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Janssen Research & Development, LLC, Spring House, PA, USA., Sinha J; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Pediatrics, UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Maglalang PD; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Edginton A; School of Pharmacy, University of Waterloo, Kitchener, ON, Canada., Gonzalez D; Division of Clinical Pharmacology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA. daniel.gonzalez@duke.edu.; Duke Clinical Research Institute, PO Box 17969, Durham, NC, 27715, USA. daniel.gonzalez@duke.edu.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2024 Oct; Vol. 63 (10), pp. 1435-1448. Date of Electronic Publication: 2024 Sep 19.
DOI: 10.1007/s40262-024-01418-8
Abstrakt: Background and Objective: Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia.
Methods: A PBPK model was first developed and evaluated in adults using PK-Sim ® and MoBi ® (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels.
Results: The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (f u ) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure.
Conclusion: The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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