{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:35:42Z","timestamp":1792136142857,"version":"4.4.0"},"reference-count":76,"publisher":"Walter de Gruyter GmbH","issue":"6","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_cclm-2025-1053_abs_001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>An isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS\/MS)-based candidate reference measurement procedure (cRMP) was developed and validated to measure serum and plasma concentrations of the total and free form of valproic\u00a0acid.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_cclm-2025-1053_abs_002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Quantitative nuclear magnetic resonance spectroscopic methodology was used to determine the absolute content (g\/g) of the reference material, ensuring traceability to SI units. Separation of valproic acid from potential unknown interferences was achieved with reversed-phase chromatography. A protein precipitation protocol was established for sample preparation for total valproic acid, while the free form was separated by ultrafiltration. Assay validations and measurement uncertainties were aligned with guidelines from the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_cclm-2025-1053_abs_003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The cRMPs were highly selective and specific with no evidence of matrix effects, allowing quantifying total and\u00a0free valproic acid in a range of 2.40\u2013145\u202f\u03bcg\/mL and 1.60\u201342.0\u202f\u03bcg\/mL, respectively. Intermediate precision was &lt;4.0\u202f% and repeatability CV ranged from 0.9 to 3.5% for all concentrations of free and total valproic acid. The relative mean bias ranged from\u00a0\u22120.4 to 4.1\u202f% for native serum and from\u00a0\u22120.3 to 3.5\u202f% for Li-heparin plasma levels for total valproic acid. Free valproic acid showed mean biases between\u00a0\u22122.9 and 4.0\u202f% for native serum and ultrafiltrates. Measurement uncertainties for single measurements and target value assignment ranged from 1.7 to 3.4\u202f% and 0.9\u20131.3\u202f%, respectively, for total valproic acid. Free valproic acid ranged from 2.0 to 4.1\u202f% and from 0.8 to 1.5\u202f% for single measurements and target value assignment, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_cclm-2025-1053_abs_004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We present novel ID-LC-MS\/MS-based cRMPs for total and free valproic acid in human serum and plasma which provides a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/cclm-2025-1053","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T11:58:01Z","timestamp":1762171081000},"page":"1238-1254","source":"Crossref","is-referenced-by-count":2,"title":["An isotope dilution-liquid-chromatography-tandem mass spectrometry-based candidate reference measurement procedure for the quantification of total and free valproic acid in human serum and plasma"],"prefix":"10.1515","volume":"64","author":[{"given":"Tobias","family":"Schierscher","sequence":"first","affiliation":[{"name":"Dr. Risch Ostschweiz AG , Buchs , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Salzmann","sequence":"additional","affiliation":[{"name":"Dr. Risch Ostschweiz AG , Buchs , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Singh","sequence":"additional","affiliation":[{"name":"111618 Roche Diagnostics GmbH , Penzberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Fleischer","sequence":"additional","affiliation":[{"name":"111618 Roche Diagnostics GmbH , Penzberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Dr. Risch Ostschweiz AG , Buchs , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hoop","sequence":"additional","affiliation":[{"name":"Dr. Risch Ostschweiz AG , Buchs , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Bauland","sequence":"additional","affiliation":[{"name":"Chrestos Concept GmbH & Co. KG , Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Geistanger","sequence":"additional","affiliation":[{"name":"111618 Roche Diagnostics GmbH , Penzberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2692-6699","authenticated-orcid":false,"given":"Lorenz","family":"Risch","sequence":"additional","affiliation":[{"name":"Dr. Risch Ostschweiz AG , Buchs , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Seger","sequence":"additional","affiliation":[{"name":"Dr. Risch Ostschweiz AG , Buchs , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Taibon","sequence":"additional","affiliation":[{"name":"111618 Roche Diagnostics GmbH , Penzberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"2026081408005209097_j_cclm-2025-1053_ref_001","unstructured":"U.S. Food and Drug Administration. 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