The Effect of Sample Handling on Free Valproic Acid Levels

2020 ◽  
Author(s):  
Dan Wang ◽  
Elizabeth Champion-Lyons ◽  
Ron Neyens ◽  
Nicole Bohm ◽  
Brittany Caddell ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Anticonvulsant Drug ◽  
Free Fraction ◽  
Free Drug ◽  
Reference Laboratory ◽  
Negative Bias ◽  
Sample Handling ◽  
Drug Levels ◽  
Parallel Testing ◽  
Significant Bias

Abstract Background Valproic acid (VPA) is a broad-spectrum anticonvulsant drug. Under normal conditions, this drug is highly protein bound. However, in patients with hypoalbuminemia, the free fraction can increase substantially while the total VPA levels remain in therapeutic range. The neurologic activity and toxicity of the drug are directly related to free drug levels. Methods Our in-house free VPA assay was validated using 20 patient samples obtained from a reference laboratory (RL1). It was further evaluated by parallel testing with RL1 using samples collected from our patients. Subsequently, sample handling effects were investigated by comparing free VPA levels measured in our laboratory to 3 selected RLs with different sample transportation conditions. Results No significant bias was observed between the in-house assay (y) and RL1 (x) assay in free VPA measurement (y = 1.12x + 0.072, r = 0.994). However, patient samples collected in our institution and sent to RL1 revealed significant negative bias (y = 0.776x − 3.861, r = 0.954). A large discrepancy in free VPA levels was further observed from identical aliquots of the same samples transported to 3 RLs in different conditions. Conclusions Our study demonstrated that sample handling has significant impact on free VPA levels. The observed magnitude of variation exceeds a clinically acceptable limit and could alter clinical decisions.

scholarly journals Microscale ultrafiltration technique for determining free drug in 50-microL serum samples.

1984 ◽  
Vol 30 (6) ◽  
pp. 878-879 ◽  
Author(s):  
W Wittfoht ◽  
K Duwe ◽  
W Kuhnz ◽  
H Nau
Keyword(s):  
Valproic Acid ◽  
Free Fraction ◽  
Free Drug ◽  
Laboratory Animals ◽  
Small Laboratory ◽  
Serum Samples

Abstract This ultrafiltration technique allows determination of free drug in 50 microL of serum. We ultrafiltered sera containing the following drugs--valproic acid (and its major metabolites), phenobarbital, diazepam, indomethacin, phenytoin, furosemide, and chloramphenicol--using both the commercially available micropartition system (MPS-1, Amicon), which requires a 200-microL sample, and our modified micro system, which requires only 50 microL. The value for the free fraction of each drug obtained in the two experiments agreed well. The smaller sample requirement makes the micro method particularly suited for pediatric samples and studies on small laboratory animals.

Micro-Scale Ultracentrifugation as an Alternative to Ultrafiltration for the Determination of the Unbound Fraction of Phenytoin in Human Serum

1986 ◽  
Vol 23 (5) ◽  
pp. 603-607 ◽  
Author(s):  
L Jack ◽  
C Cunningham ◽  
I D Watson ◽  
M J Stewart
Keyword(s):  
Human Serum ◽  
Simple Procedure ◽  
Free Fraction ◽  
Free Drug ◽  
Effect Of Temperature ◽  
Unbound Fraction ◽  
Drug Levels ◽  
Micro Scale ◽  
Great Utility

Free phenytoin has been determined using micro-scale ultracentrifugation followed by analysis by EMIT. The effect of temperature on the determined free fraction was investigated and the ultracentrifugation procedure validated against ultrafiltration. Ultracentrifugation gave free fractions which were on average 16% lower than those obtained using ultrafiltration, but correlation was good, as was the correlation with measurements of total phenytoin ( r=0·90). Micro-scale ultracentrifugation is a simple procedure which can be of great utility in the measurement and investigation of free drug levels.

scholarly journals The Wild West of Emergency Use Authorizations for SARS-CoV-2 Testing: What Could Be the True Sensitivity?

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S142-S143
Author(s):  
S Dalal ◽  
S Patel ◽  
J M Petersen ◽  
D Jhala
Keyword(s):  
Medical Center ◽  
Initial Result ◽  
Reference Laboratory ◽  
Test Results ◽  
Rt Pcr ◽  
Repeat Testing ◽  
Parallel Testing ◽  
Percent Agreement ◽  
Instructions For Use ◽  
Multiple Reference

Abstract Introduction/Objective SARS-CoV-2 is a pandemic that has required mobilization to meet urgent needs. In this mobilization, emergency use authorizations (EUA) have been issued by the FDA to expedite the deployment of these tests. This has led to a situation whereby sensitivity has not been rigorously studied for any of the assays with EUAs. Estimates can be extrapolated from the limited samples documented by the company in their instructions for use (IFU). Although the nationwide shortage of testing reagents prevent parallel testing of multiple platforms on all specimens, observations of repeat specimens at the Veteran Affairs Medical Center (VAMC) provides the first study in the literature of more complete data for SARS-CoV-2 nucleic acid (RT-PCR) assay on sensitivity on the Abbott (Abbott Park Ill) and Cepheid (Sunnyvale CA) assays. Methods A retrospective search was performed for all test results for SARS-CoV-2 by RT-PCR from 3/1/2020 to 4/14/2020 at Corporal Michael J. Crescenz Medical Center, in order to evaluate the sensitivity on Abbott m2000 and Cepheid platforms. Results across multiple reference laboratories and in-house testing platforms were collated in a table with all patients clinically requiring repeat testing recorded. Results 114/863 patients had repeat testing. The tests were performed initially by outside reference laboratories (25 patients), on the Abbott m2000 (63 patients), and Cepheid Infinity (26 patients). 15/114 (13%) had discordant results on repeat testing. This included 1 test initially done by a reference laboratory. 8 days after the initial result from the reference lab, a positive for the same patient was identified on the Abbott platform. 11 initial Abbott results were discordant on further repeat testing on two platforms - Abbott (6 patients) and Cepheid (5 patients) 1-6 days later. In addition, 3 initial Cepheid were discordant on further repeat testing by the same Cepheid platform (1-16 days later). Conclusion While the instructions for use for both platforms suggest 100% sensitivity and specificity (due to the 100% positive and negative percent agreement in limited specimens), the true sensitivity is less than 100%, particularly early in the course of the infection. In our study, the positive percent agreement (surrogate for sensitivity) was 83% for initial Abbott tests, 88% for initial Cepheid tests, and 95% by Reference laboratory platform.

Reversible cognitive impairment associated with a high free fraction but subtherapeutic total blood level of valproic acid due to hypoalbuminemia in a bipolar patient

2017 ◽  
Vol 41 (S1) ◽  
pp. S420-S420
Author(s):  
G. Dautzenberg ◽  
M. Nederlof ◽  
E. Heerdink ◽  
A. Beekman
Keyword(s):  
Valproic Acid ◽  
Cognitive Impairment ◽  
Binding Capacity ◽  
Free Fraction ◽  
Bipolar Patient ◽  
Therapeutic Drug ◽  
Blood Levels ◽  
Reference Ranges ◽  
Total Blood ◽  
Pharmacologically Active

Valproic acid (VPA) is widely used in the treatment of epilepsy and bipolar disorder. It is largely bound to serum proteins (80–95%) in particular albumin, with a saturable binding capacity. Under conditions of hypoalbuminemia, protein binding of VPA will decrease and its pharmacologically-active free fraction will rise, even to toxic levels while measuring subtherapeutic VPA total blood levels [1].We present an elderly bipolar patient with (sub)clinical total levels of VPA and a high free fraction of VPA due to hypoalbuminemia (14–24 g/L) leading to severe reversible cognitive impairment.VPA and the free fraction in particular, was the most likely cause of the cognitive impairment [2]. There was a time-correlation with increasing blood levels of total VPA (68 mg/L, reference 80–120 mg/L [3]), notably the free fraction (37.5 mg/L, reference 5–15 mg/L), and the intoxication.For therapeutic drug monitoring in laboratories, generally, total VPA concentrations (free + protein-bound) are measured instead of free fractions, due to technical difficulties, a lack of established reference ranges [4] and (inter)national guidelines [5,6] not requiring it. This presentation and literature points out that it is clinically relevant to measure the free fraction [7,8], especially in patients with hypoalbuminemia [9–11] to prevent unnecessary side effects and toxicity.We recommend measuring albumin during VPA use; particularly in patients with nephrotic syndrome, liver disease [12] or older adults [13–15]. Hypoalbuminemia demands a free fraction measurement.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Clinical studies on serum concentration of free fraction of phenytoin, carbamazepine and valproic acid.

1990 ◽  
Vol 16 (5) ◽  
pp. 277-287 ◽  
Author(s):  
JUN HOSOYA ◽  
HIDEYO NAGAOKA ◽  
SYU ISHIKAWA ◽  
YOSHITO NAKAGAWA ◽  
YOSHIAKI HIGASHITANI ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Serum Concentration ◽  
Clinical Studies ◽  
Free Fraction

scholarly journals MONITORING OF ANTICONVULSANT DRUG SIDE EFFECTS IN OUTPATIENTS WITH EPILEPSY

2018 ◽  
Vol 10 (1) ◽  
pp. 303
Author(s):  
Santi Purna Sari ◽  
Natasha Kurnia Salma S ◽  
Alfina Rianti
Keyword(s):  
Valproic Acid ◽  
Side Effects ◽  
Medical Records ◽  
Side Effect ◽  
Anticonvulsant Drug ◽  
Secondary Data ◽  
Drug Side Effects ◽  
Inclusion Criteria ◽  
Descriptive Data ◽  
Effect Monitoring

Objective: This study aimed to monitor the side effects of carbamazepine, phenytoin, and valproic acid, and combinations of these drugs in adultpatients with epilepsy, to raise awareness of the importance of drug side effect monitoring in hospitals.Methods: In this prospective study, descriptive data were collected from patients who met the inclusion criteria of complete samples. Primary datawere obtained using questionnaires, secondary data were collected from medical records, and analyses were performed using the Naranjo algorithm.Results: Among the 54 included patients, 38 (70.37%) of them experienced drug side effects, and the most frequently observed side effect occurredin 48.15% of study subjects.Conclusion: No correlation was identified between side effects and age (p=0.903) or gender (p=1.000).

Apparent Valproic Acid Neurotoxicity in a Hypoalbuminemic Patient

1993 ◽  
Vol 27 (1) ◽  
pp. 32-35 ◽  
Author(s):  
Barry E. Gidal ◽  
D. Michael Collins ◽  
Brad R. Beinlich
Keyword(s):  
Valproic Acid ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Plasma Concentrations ◽  
Free Fraction ◽  
Laboratory Evaluation ◽  
Neurologic Symptoms ◽  
Drug Concentrations ◽  
Dependent Protein

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 μg/mL, which was only slightly above the recommended therapeutic range (50–100 μg/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 μg/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

Valproic acid: an anticonvulsant drug with potent antinociceptive and anti-inflammatory properties

2013 ◽  
Vol 386 (7) ◽  
pp. 575-587 ◽  
Author(s):  
José Christian Machado Ximenes ◽  
Danilo de Oliveira Gonçalves ◽  
Rafaelly Maria Pinheiro Siqueira ◽  
Kelly Rose Tavares Neves ◽  
Gilberto Santos Cerqueira ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Anticonvulsant Drug ◽  
Anti Inflammatory
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