Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review

Lin, Kevin B.L.; Cao, Vivien; Au, Charles; Dahri, Karen

doi:10.1007/s40262-022-01171-w

Cited by 9 publications

(10 citation statements)

References 64 publications

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“…It is generally safe and may be given orally or intravenously 9. Lin et al conducted a systematic review exploring the relationship between VPA serum levels and clinical toxicity, concluding that hyperammonaemia occurs at free VPA levels above 60 umol/L 10…”

Section: Discussionmentioning

confidence: 99%

Unusual case of sodium valproate-induced hyperammonaemia encephalopathy

Ranjith,

Abeysundera,

Jeyaranjan

2023

BMJ Case Rep

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There is limited information about sodium valproate-induced hyperammonaemia encephalopathy (VPAIHE). The aim of this case report is to provide medical practitioners with a greater awareness of the possible development of hyperammonaemia due to sodium valproate use and its associated complications.This paper describes a middle-aged man with a history of bipolar affective disorder who was admitted with a manic relapse secondary to medication non-compliance. His admission was complicated by an intensive care unit admission to manage medical compromise in the context of sodium VPAIHE.

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Section: Discussionmentioning

confidence: 99%

Unusual case of sodium valproate-induced hyperammonaemia encephalopathy

Ranjith,

Abeysundera,

Jeyaranjan

2023

BMJ Case Rep

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“…Prior evaluations have identified that antipyretic doses of aspirin may cause a four-fold increase in valproate free fraction, and a similar effect may be seen with lower cardio protective doses (7,20,21). Furthermore, concomitant administration of free fatty acids containing medications (i.e., propofol or clevidipine) or IV fat emulsion itself may increase valproate free fraction, due to valproate structural similarity to free fatty acids, in a concentration-dependent manner by 19-118% (7,22).…”

Section: Observational Studymentioning

confidence: 99%

“…Valproate is highly protein-bound to albumin, with the biologically active free (unbound) fraction expected to be 5-10% of the total concentration (6,7).…”

mentioning

confidence: 99%

“…The resultant therapeutic discordance may lead to erroneous dose adjustments when guided by total VPAC alone (9)(10)(11). Free VPAC monitoring is warranted in these patients given significant interindividual variability to prevent dose-related toxicities associated with increased free VPAC (6)(7)(8).…”

mentioning

confidence: 99%

“…Valproate is highly protein-bound to albumin, with the biologically active free (unbound) fraction expected to be 5–10% of the total concentration (6, 7). The protein binding of valproate is altered by hypoalbuminemia, uremia, increasing total VPAC, free fatty acid-containing therapies (e.g., propofol, clevidipine, IV fat emulsion), and medications (e.g., aspirin) resulting in an increased free fraction (6–8). ICU patients and others at risk for altered protein binding have consistently shown much higher free fractions ranging from 15% to 89% (9).…”

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confidence: 99%

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Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

Liu,

Brown,

Mara

et al. 2023

Critical Care Explorations

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IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, –13.6 to 14.2]) than the Nasreddine (–9.2 [–26.5 to 8.2]), Kodama (–9.7 [–30.0 to 10.7]), Conde Giner (–7.9 [–24.9 to 9.1]), and Parent (–9.9 [–30.7 to 11.0]) equations, and similar to Doré (–2.0 [–16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

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Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid

Gu,

Zhang,

Yuan

et al. 2024

Clinical Laboratory Analysis

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ObjectiveThis study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co‐administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA.MethodsWe retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co‐administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co‐administerd VPA and other broad‐spectrum antibiotics were allocated to the control group.ResultsThe exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co‐administration (24.6 ± 4.3 μg/mL) compared with that before co‐administration (88.8 ± 13.6 μg/mL, p < 0.0001), and it was partly recovered with the termination of co‐administration (39.8 ± 13.2 μg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before‐during and before‐after (p = 0.074 and 0.153, respectively). Seizure duration during VPA–MEPM co‐administration was not significantly different from that before co‐administration (p = 0.291).ConclusionsIn this study, the reduced plasma concentration of VPA induced by the co‐administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted.Trial RegistrationChinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020

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Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review

Cited by 9 publications

References 64 publications

Unusual case of sodium valproate-induced hyperammonaemia encephalopathy

Unusual case of sodium valproate-induced hyperammonaemia encephalopathy

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid

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