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Development and validation of an analytical method using UPLC-MS/MS to quantify everolimus in dried blood spots in the oncology setting.
J Pharm Biomed Anal 2018; 149:106-113JP

Abstract

While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated. An 7.5mm disk from the central part of the DBS was punched, followed by the extraction of everolimus from the DBS by methanol/acetonitrile (80/20%) spiked with deuterium-labelled everolimus as internal standard. Subsequently, everolimus was separated and analyzed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The UPLC-MS/MS method was validated according to the European Medicine Agency (EMA) guideline. Everolimus concentrations could be quantified over the range of 3-75μg/L. The intra- and inter-assay precision and accuracy of the method were shown to be acceptable (coefficient of variation ≤10.7% and relative error ≤4.4%, respectively). The matrix effects appeared to be influenced by the hematocrit effect. The hematocrit effect was tested in a range of 0.20-0.50L/L, at which hematocrit accuracy and precision were satisfactory at values ≥0.25L/L. However, at 0.20L/L hematocrit in combination with high everolimus concentrations of 20 and 40μg/L, the precision was adequate (≤7.4%), but the accuracy was >15% of the nominal concentration. Everolimus was stable in DBS for at least 80days at 2-8°C. Given these results, the everolimus DBS method has been successfully developed and validated. Special attention is necessary for cancer patients with both a 0.20L/L hematocrit in combination with everolimus concentrations ≥20μg/L. A clinical validation for the use of everolimus DBS in cancer patients is currently being undertaken.

Authors+Show Affiliations

Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, P.O. BOX 5800, 6202 AZ, Maastricht, The Netherlands; CAPHRI-Care And Primary Health Research Institute, Maastricht University Medical Center+, P.O. BOX 616, 6200 MD, Maastricht, The Netherlands.Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, P.O. BOX 5800, 6202 AZ, Maastricht, The Netherlands.Department of Pharmacy, Radboud University Medical Center, P.O. BOX 9101, 6500 HB, Nijmegen, The Netherlands.Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, P.O. BOX 5800, 6202 AZ, Maastricht, The Netherlands; CAPHRI-Care And Primary Health Research Institute, Maastricht University Medical Center+, P.O. BOX 616, 6200 MD, Maastricht, The Netherlands.Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, P.O. BOX 5800, 6202 AZ, Maastricht, The Netherlands; CAPHRI-Care And Primary Health Research Institute, Maastricht University Medical Center+, P.O. BOX 616, 6200 MD, Maastricht, The Netherlands; Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, P.O. BOX 80082, 3508 TB, Utrecht, The Netherlands; MRC Lifecourse Epidemiology Unit, Southampton General Hospital, University of Southampton, SO16 6YD, UK.Department of Medical Oncology, Maastricht University Medical Center+, P.O. BOX 5800, 6202 AZ, Maastricht, The Netherlands; GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, P.O. BOX 616, 6200 MD, Maastricht, The Netherlands.Department of Pharmacy, Radboud University Medical Center, P.O. BOX 9101, 6500 HB, Nijmegen, The Netherlands.Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, P.O. BOX 5800, 6202 AZ, Maastricht, The Netherlands; CAPHRI-Care And Primary Health Research Institute, Maastricht University Medical Center+, P.O. BOX 616, 6200 MD, Maastricht, The Netherlands. Electronic address: s.croes@mumc.nl.

Pub Type(s)

Journal Article
Validation Study

Language

eng

PubMed ID

29112898

Citation

Knapen, Lotte M., et al. "Development and Validation of an Analytical Method Using UPLC-MS/MS to Quantify Everolimus in Dried Blood Spots in the Oncology Setting." Journal of Pharmaceutical and Biomedical Analysis, vol. 149, 2018, pp. 106-113.
Knapen LM, Beer Y, Brüggemann RJM, et al. Development and validation of an analytical method using UPLC-MS/MS to quantify everolimus in dried blood spots in the oncology setting. J Pharm Biomed Anal. 2018;149:106-113.
Knapen, L. M., Beer, Y., Brüggemann, R. J. M., Stolk, L. M., Vries, F., Tjan-Heijnen, V. C. G., ... Croes, S. (2018). Development and validation of an analytical method using UPLC-MS/MS to quantify everolimus in dried blood spots in the oncology setting. Journal of Pharmaceutical and Biomedical Analysis, 149, pp. 106-113. doi:10.1016/j.jpba.2017.10.039.
Knapen LM, et al. Development and Validation of an Analytical Method Using UPLC-MS/MS to Quantify Everolimus in Dried Blood Spots in the Oncology Setting. J Pharm Biomed Anal. 2018 Feb 5;149:106-113. PubMed PMID: 29112898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development and validation of an analytical method using UPLC-MS/MS to quantify everolimus in dried blood spots in the oncology setting. AU - Knapen,Lotte M, AU - Beer,Yvo de, AU - Brüggemann,Roger J M, AU - Stolk,Leo M, AU - Vries,Frank de, AU - Tjan-Heijnen,Vivianne C G, AU - Erp,Nielka P van, AU - Croes,Sander, Y1 - 2017/10/29/ PY - 2017/06/29/received PY - 2017/10/26/revised PY - 2017/10/28/accepted PY - 2017/11/8/pubmed PY - 2018/7/28/medline PY - 2017/11/8/entrez KW - Analytical method KW - Dried blood spot testing KW - Everolimus KW - Hematocrit KW - Oncology KW - UPLC–MS/MS SP - 106 EP - 113 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 149 N2 - While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated. An 7.5mm disk from the central part of the DBS was punched, followed by the extraction of everolimus from the DBS by methanol/acetonitrile (80/20%) spiked with deuterium-labelled everolimus as internal standard. Subsequently, everolimus was separated and analyzed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The UPLC-MS/MS method was validated according to the European Medicine Agency (EMA) guideline. Everolimus concentrations could be quantified over the range of 3-75μg/L. The intra- and inter-assay precision and accuracy of the method were shown to be acceptable (coefficient of variation ≤10.7% and relative error ≤4.4%, respectively). The matrix effects appeared to be influenced by the hematocrit effect. The hematocrit effect was tested in a range of 0.20-0.50L/L, at which hematocrit accuracy and precision were satisfactory at values ≥0.25L/L. However, at 0.20L/L hematocrit in combination with high everolimus concentrations of 20 and 40μg/L, the precision was adequate (≤7.4%), but the accuracy was >15% of the nominal concentration. Everolimus was stable in DBS for at least 80days at 2-8°C. Given these results, the everolimus DBS method has been successfully developed and validated. Special attention is necessary for cancer patients with both a 0.20L/L hematocrit in combination with everolimus concentrations ≥20μg/L. A clinical validation for the use of everolimus DBS in cancer patients is currently being undertaken. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/29112898/Development_and_validation_of_an_analytical_method_using_UPLC_MS/MS_to_quantify_everolimus_in_dried_blood_spots_in_the_oncology_setting_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0731-7085(17)31689-8 DB - PRIME DP - Unbound Medicine ER -