Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2024 Nov;80(11):1751-1759.
doi: 10.1007/s00228-024-03741-2. Epub 2024 Aug 16.

Therapeutic drug monitoring for valproate: deriving a novel formula for calculation of free concentration

Erna Pretorius  1 , Paulina van Zyl  2 , Gina Joubert  3
Affiliations
Observational Study

Therapeutic drug monitoring for valproate: deriving a novel formula for calculation of free concentration

Erna Pretorius et al. Eur J Clin Pharmacol. 2024 Nov.

Abstract

Background: Monitoring free valproate concentrations, as with other highly protein-bound anticonvulsants, is essential in clinical situations where protein binding may be disrupted. Conversion of measured total concentrations to approximate free concentrations offers a cost-effective alternative. This study evaluated the relationship between total and free valproate concentrations for discordance and the impact of key determinants. A novel formula was devised that incorporates significant variables.

Methods: A multicentre, cross-sectional observational analytical study included 101 subjects 18 years and older using valproate for 6 months or longer. Participants were recruited from private and public sector healthcare settings from primary to tertiary level in, South Africa, during 2017-2019.

Results: Free valproate concentrations could be measured for 84 subjects. Discordance for concomitant total and free valproate concentrations was 79.1%. Among 19 participants with elevated free concentrations, 15 (78.9%) had total valproate concentrations within the recommended reference range. Calculations based on the study-derived formula were more accurate in predicting free valproate concentration than previously proposed methods.

Conclusion: This study proposes that the novel formula for calculating free valproate enables more accurate prediction.

Keywords: Calculation; Formula; Free concentration; Therapeutic drug monitoring; Total concentration; Valproate.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Relationship between free valproic acid and total valproic acid concentrations (n = 84). The red trendline presents the polynomial correlation, and the green line presents the linear correlation
Fig. 2
Fig. 2
Scatter plot of the relationship between valproic acid free fraction (%) plotted against total valproic acid concentration (µg/mL). The red trendline represents a polynomial correlation
Fig. 3
Fig. 3
Median albumin (g/L) concentration plotted against age grouped in 10-year intervals (n = 84)
Fig. 4
Fig. 4
Scatter plot of the relationship between the estimated free valproic acid concentration using the new study-derived formula, compared to the measured free valproic acid concentration. The dotted red trendline presents the data according to a linear equation
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Rahman M, Awosika AO, Nguyen H (2024) Valproic acid. StatPearls Publishing, Treasure Island, FL - PubMed
    1. Lampon N, Tutor J (2012) Apparent clearance of valproic acid in elderly epileptic patients: estimation of the confounding effect of albumin concentration. Ups J Med Sci 117(1):41–46. 10.3109/03009734.2011.640412 - PMC - PubMed
    1. Nasreddine W, Dirani M, Atweh S, Makki A, Beydoun A (2018) Determinants of free serum valproate concentration: a prospective study in patients on divalproex sodium monotherapy. Seizure 59:24–27. 10.1016/j.seizure.2018.04.012 - PubMed
    1. Patsalos P, Zugman M, Lake C, James A, Ratnaraj N, Sander J (2017) Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: a comparison of free non-protein-bound concentrations. Epilepsia 58(7):1234–1243. 10.1111/epi.13802 - PubMed
    1. Musteata FM (2017) Measuring and using free drug concentrations: has there been ‘real’ progress? Bioanalysis 9(10):767–769. 10.4155/bio-2017-0053 - PubMed

Publication types

LinkOut - more resources