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Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting.
Ther Drug Monit. 2018 08; 40(4):469-476.TD

Abstract

BACKGROUND

Therapeutic drug monitoring of antiepileptic drugs (AEDs) is often necessary to prevent associated destructive toxicities. Tandem mass spectrometry (MS/MS) with stable-isotope-labeled internal standards is considered the gold standard for the measurement of AEDs. This study presents the development and validation of a clinical ultra-performance liquid chromatography-MS/MS method for the concurrent measurement of gabapentin, lamotrigine, levetiracetam, monohydroxy derivative of oxcarbazepine, and zonisamide in human serum.

METHODS

To determine the optimal assay analyte range, one year of AED therapeutic drug monitoring results (n = 1825) were evaluated. Simple protein precipitation with acetonitrile containing isotopically labeled internal standards was used. Reverse-phase ultra-performance liquid chromatography chromatographic separation was used, having a total run time of 3 minutes. Quantification of analytes was accomplished using electrospray ionization in positive ion mode and collision-induced dissociation MS. Assay parameters were evaluated per Food and Drug Administration bioanalytical guidelines.

RESULTS

After evaluating internal patient data, the analytical measuring range (AMR) of the assay was established as 0.1-100 mcg/mL. All AEDs were linear across the AMR, with R values ranging from 0.9988 to 0.9999. Imprecision (% coefficient of variation) and inaccuracy (% difference) were calculated to be <20% for the lower limit of quantitation and <15% for the low, mid, and high levels of quality controls across the AMR. All AEDs demonstrated acceptable assay parameters for carryover, stability under relevant storage conditions, matrix effects, recovery, and extraction and processing efficiency. In addition, the assay displayed acceptable concordance to results obtained from a national reference laboratory, with Deming regression R of 0.99 and slope values ranging from 0.89 to 1.17.

CONCLUSIONS

A simple, cost-effective, and robust ultra-performance liquid chromatography-tandem mass spectrometry method for monitoring multiple AEDs was developed and validated to address the clinical needs of patients at our institution.

Links

Authors+Show Affiliations

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School.

Department of Pathology, Brigham and Women's Hospital, Boston, MA.

Waters Corporation, Milford, MA.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School.

MeSH

AnticonvulsantsChromatography, High Pressure LiquidChromatography, Reverse-PhaseDrug MonitoringGabapentinHumansLamotrigineLevetiracetamLimit of DetectionOxcarbazepineReproducibility of ResultsTandem Mass SpectrometryZonisamide

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Validation Study

Language

eng

PubMed ID

29994986

Citation

Palte, Michael J., et al. "Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting." Therapeutic Drug Monitoring, vol. 40, no. 4, 2018, pp. 469-476.

Palte MJ, Basu SS, Dahlin JL, et al. Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting. Ther Drug Monit. 2018;40(4):469-476.

Palte, M. J., Basu, S. S., Dahlin, J. L., Gencheva, R., Mason, D., Jarolim, P., & Petrides, A. K. (2018). Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting. Therapeutic Drug Monitoring, 40(4), 469-476. https://doi.org/10.1097/FTD.0000000000000516

Palte MJ, et al. Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting. Ther Drug Monit. 2018;40(4):469-476. PubMed PMID: 29994986.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting. AU - Palte,Michael J, AU - Basu,Sankha S, AU - Dahlin,Jameson L, AU - Gencheva,Ralitsa, AU - Mason,Donald, AU - Jarolim,Petr, AU - Petrides,Athena K, PY - 2018/7/12/entrez PY - 2018/7/12/pubmed PY - 2019/1/1/medline SP - 469 EP - 476 JF - Therapeutic drug monitoring JO - Ther Drug Monit VL - 40 IS - 4 N2 - BACKGROUND: Therapeutic drug monitoring of antiepileptic drugs (AEDs) is often necessary to prevent associated destructive toxicities. Tandem mass spectrometry (MS/MS) with stable-isotope-labeled internal standards is considered the gold standard for the measurement of AEDs. This study presents the development and validation of a clinical ultra-performance liquid chromatography-MS/MS method for the concurrent measurement of gabapentin, lamotrigine, levetiracetam, monohydroxy derivative of oxcarbazepine, and zonisamide in human serum. METHODS: To determine the optimal assay analyte range, one year of AED therapeutic drug monitoring results (n = 1825) were evaluated. Simple protein precipitation with acetonitrile containing isotopically labeled internal standards was used. Reverse-phase ultra-performance liquid chromatography chromatographic separation was used, having a total run time of 3 minutes. Quantification of analytes was accomplished using electrospray ionization in positive ion mode and collision-induced dissociation MS. Assay parameters were evaluated per Food and Drug Administration bioanalytical guidelines. RESULTS: After evaluating internal patient data, the analytical measuring range (AMR) of the assay was established as 0.1-100 mcg/mL. All AEDs were linear across the AMR, with R values ranging from 0.9988 to 0.9999. Imprecision (% coefficient of variation) and inaccuracy (% difference) were calculated to be <20% for the lower limit of quantitation and <15% for the low, mid, and high levels of quality controls across the AMR. All AEDs demonstrated acceptable assay parameters for carryover, stability under relevant storage conditions, matrix effects, recovery, and extraction and processing efficiency. In addition, the assay displayed acceptable concordance to results obtained from a national reference laboratory, with Deming regression R of 0.99 and slope values ranging from 0.89 to 1.17. CONCLUSIONS: A simple, cost-effective, and robust ultra-performance liquid chromatography-tandem mass spectrometry method for monitoring multiple AEDs was developed and validated to address the clinical needs of patients at our institution. SN - 1536-3694 UR - https://www.unboundmedicine.com/medline/citation/29994986/Development_and_Validation_of_an_Ultra_Performance_Liquid_Chromatography_Tandem_Mass_Spectrometry_Method_for_the_Concurrent_Measurement_of_Gabapentin_Lamotrigine_Levetiracetam_Monohydroxy_Derivative_of_Oxcarbazepine_and_Zonisamide_Concentrations_in_Serum_in_a_Clinical_Setting_ DB - PRIME DP - Unbound Medicine ER -