Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

Doré, Monique; Juan, Adriana E. San; Frenette, Anne Julie

doi:10.1002/phar.1965

Cited by 37 publications

(37 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…High levels of free concentration are associated with higher risk of toxicity. 12,41 Because of the variability of unbound concentration, limitations in the interpretation of total serum concentration are expected, with potential discordance between total and free concentration. 14,41 Quantifying free concentration might be relevant in some patients, for example, in cases of suspicion of toxicity, polytherapy, hypoalbuminemia, or renal failure.…”

Section: Discussionmentioning

confidence: 99%

“…14,41 Quantifying free concentration might be relevant in some patients, for example, in cases of suspicion of toxicity, polytherapy, hypoalbuminemia, or renal failure. 12 Because serum albumin concentration increases with age in children 42 and unbound concentration of valproate correlates with albumin concentration, 12 we could expect valproate free concentration to vary according to age. Nevertheless, no relationship between age and unbound valproate concentration has been reported in the literature yet, 43 and the decrease of clearance with increasing age seems to be mostly because of maturational changes in hepatic metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…4,10 The other consequence of saturable binding is an increase in the unbound concentration that can result in higher toxicity risk. 12 Its volume of distribution in children is around 0.3 L/kg. [13][14][15] VPA is almost entirely metabolized by microsomal glucuronide conjugation, mitochondrial and cytochrome P450dependent oxidation.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Tauzin

Tréluyer

Nabbout

et al. 2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128 mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6 mg/L and a root mean squared error of 25.1 mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50 mg/L. Simulations suggested increasing doses, especially for children ࣘ40 kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Tauzin

Tréluyer

Nabbout

et al. 2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…VPA also modulates neurotransmitters such as dopamine, serotonin, and voltage-gated ion channels such as sodium, calcium, and potassium channels that stabilize neuronal membranes [2]. Concerning pharmacokinetics, VPA typically has high bioavailability (90%), and albumin binding is commonly reported at 90%, but it may be much less than this in specific situations, including in low albumin states, with elevated blood urea nitrogen (BUN), and with medications that compete for binding such as lipid emulsion agents, aspirin, and phenytoin [3][4][5][6]. VPA is extensively metabolized by the liver through glucuronidation (50%), mitochondrial β-oxidation (40%), and other pathways.…”

Section: Introductionmentioning

confidence: 99%

Safety range of free valproic acid serum concentration in adult patients

et al. 2020

View full text Add to dashboard Cite

Background Therapeutic drug monitoring (TDM) is recommended during valproic acid (VPA) use, and total serum concentration has been widely adopted. However, the free form of VPA is responsible for its pharmacologic and toxic effects, and the total and free concentrations are highly discordant because of VPA's highly protein bound and saturable binding characteristics. Therefore, free VPA monitoring is increasingly advocated. Nevertheless, the correlation between free VPA concentration and associated adverse effects remains unknown. Objective To determine the optimal safety range of free VPA concentration in adult patients. Materials and methods This prospective cohort study enrolled adult patients undergoing VPA therapy with TDM. Patient characteristics, VPA use, and adverse effects (thrombocytopenia, hyperammonemia, and hepatotoxicity) were recorded. A multivariate logistic regression model was applied to identify the predictors of adverse effects, and the receiver operating characteristic curve was applied to locate the cutoff point of free VPA concentration. Results A total of 98 free serum concentrations from 51 patients were included for final analysis. In total, 31 (31.6%), 27 (27.6%), and 4 (4.1%) episodes of hyperammonemia, thrombocytopenia, and hepatotoxicity were observed, respectively. Free VPA concentration was a predicting factor for thrombocytopenia but not for hyperammonemia. A free VPA concentration of >14.67 mcg/mL had the greatest discriminating power (area under the curve = 0.77) for the occurrence of thrombocytopenia.

show abstract

“…Many studies have shown that monitoring the total valproic acid concentration can be misleading, because it can be normal or even low despite high concentrations of free valproic acid (11). If dosages are adjusted on the basis of total valproic acid levels, patients who are hypoalbuminemic can be overdosed, leading to clinically significant neurologic symptoms or toxicity (10,15). Thus, there is greater clinical utility and importance in monitoring the free valproic acid concentration, rather than the total, in patients with hypoalbuminemia (3,4,11).…”

Section: Valproic Acid Toxicitymentioning

confidence: 99%

Valproate Monitoring in Patients With Hypoalbuminemia

Han

2019

AJP Residents' Journal

View full text Add to dashboard Cite

A 50-year-old man with a history of schizoaffective disorder, bipolar type, diabetes mellitus type 2, chronic kidney disease stage 3, and hypertension was brought to the emergency department for swelling of his face and extremities, questionable medication compliance, and recent unusual and threatening behavior. His psychiatric medications included divalproex sodium extendedrelease (2,000 mg nightly), long-acting injectable risperidone (25 mg every 2 weeks), and trazodone (100 mg nightly). The patient had been stable on this regimen for many years before the days leading up to his presentation in the emergency department. His total valproic acid level on presentation was 65 µg/ mL. His complete blood count was unremarkable. His basic metabolic panel was notable for blood urea nitrogen (22 mg/dL), his creatinine level was 2.1 mg/ dL, his estimated glomerular filtration rate was 34, his aspartate aminotransferase level was 65 IU/L, and his alanine aminotransferase level was 97 IU/L. The patient's urine drug screen was negative, and an ECG was unremarkable. He weighed 183 lbs and had a body mass index of 28. His bilateral lower extremities showed edema of 1+, and a neurological examination was unremarkable. Further workup revealed nephrotic syndrome with an albumin level of 2.2 g/dL (normal range, 3.6-4.8 g/dL).

show abstract

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

Cited by 37 publications

References 26 publications

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

Safety range of free valproic acid serum concentration in adult patients

Valproate Monitoring in Patients With Hypoalbuminemia

Contact Info

Product

Resources

About