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Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study.
J Pharm Biomed Anal 2020; 179:113002JP

Abstract

Cefepime is a fourth-generation cephalosporin antibiotic with an extended spectrum of activity against many Gram-positive and Gram-negative bacteria. There is a growing need to develop sensitive, small volume assays, along with less invasive sample collection to facilitate pediatric pharmacokinetic clinical trials and therapeutic drug monitoring. The volumetric absorptive microsampling (VAMS™) approach provides an accurate and precise collection of a fixed volume of blood (10 μL), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed a high-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of cefepime. Sample extraction from VAMS™ devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4 min runtime per sample was employed. Standard curves were linear between 0.1-100 μg/mL for cefepime. Intra- and inter-day accuracies were within 95.4-113% and precision (CV) was < 15 % based on a 3-day validation study. Recoveries ranged from 40.8 to 62.1% and the matrix effect was within 89.5-96.7% for cefepime. Cefepime was stable in human whole blood under assay conditions (3 h at room temperature, 24 h in autosampler post-extraction). Cefepime was also stable for at least 1 week (7 days) at 4 °C, 1 month (39 days) at -20 °C and 3 months (91 days) at -78 °C as dried microsamples. This assay provides an efficient quantitation of cefepime and was successfully implemented for the analysis of whole blood microsamples in a pediatric clinical trial.

Authors+Show Affiliations

Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States. Electronic address: moorthyg@email.chop.edu.Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States.Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States.Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, United States.Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States.Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States.Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States; Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31785929

Citation

Moorthy, Ganesh S., et al. "Development and Validation of a Volumetric Absorptive Microsampling- Liquid Chromatography Mass Spectrometry Method for the Analysis of Cefepime in Human Whole Blood: Application to Pediatric Pharmacokinetic Study." Journal of Pharmaceutical and Biomedical Analysis, vol. 179, 2020, p. 113002.
Moorthy GS, Vedar C, Zane NR, et al. Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study. J Pharm Biomed Anal. 2020;179:113002.
Moorthy, G. S., Vedar, C., Zane, N. R., Downes, K. J., Prodell, J. L., DiLiberto, M. A., & Zuppa, A. F. (2020). Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study. Journal of Pharmaceutical and Biomedical Analysis, 179, p. 113002. doi:10.1016/j.jpba.2019.113002.
Moorthy GS, et al. Development and Validation of a Volumetric Absorptive Microsampling- Liquid Chromatography Mass Spectrometry Method for the Analysis of Cefepime in Human Whole Blood: Application to Pediatric Pharmacokinetic Study. J Pharm Biomed Anal. 2020 Feb 5;179:113002. PubMed PMID: 31785929.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study. AU - Moorthy,Ganesh S, AU - Vedar,Christina, AU - Zane,Nicole R, AU - Downes,Kevin J, AU - Prodell,Janice L, AU - DiLiberto,Mary Ann, AU - Zuppa,Athena F, Y1 - 2019/11/20/ PY - 2019/06/25/received PY - 2019/11/18/revised PY - 2019/11/19/accepted PY - 2021/02/05/pmc-release PY - 2019/12/2/pubmed PY - 2019/12/2/medline PY - 2019/12/2/entrez KW - Cefepime KW - Human whole blood KW - Liquid chromatography KW - Mass spectrometry KW - Volumetric absorptive microsampling (VAMS™) SP - 113002 EP - 113002 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 179 N2 - Cefepime is a fourth-generation cephalosporin antibiotic with an extended spectrum of activity against many Gram-positive and Gram-negative bacteria. There is a growing need to develop sensitive, small volume assays, along with less invasive sample collection to facilitate pediatric pharmacokinetic clinical trials and therapeutic drug monitoring. The volumetric absorptive microsampling (VAMS™) approach provides an accurate and precise collection of a fixed volume of blood (10 μL), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed a high-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of cefepime. Sample extraction from VAMS™ devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4 min runtime per sample was employed. Standard curves were linear between 0.1-100 μg/mL for cefepime. Intra- and inter-day accuracies were within 95.4-113% and precision (CV) was < 15 % based on a 3-day validation study. Recoveries ranged from 40.8 to 62.1% and the matrix effect was within 89.5-96.7% for cefepime. Cefepime was stable in human whole blood under assay conditions (3 h at room temperature, 24 h in autosampler post-extraction). Cefepime was also stable for at least 1 week (7 days) at 4 °C, 1 month (39 days) at -20 °C and 3 months (91 days) at -78 °C as dried microsamples. This assay provides an efficient quantitation of cefepime and was successfully implemented for the analysis of whole blood microsamples in a pediatric clinical trial. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/31785929/Development_and_validation_of_a_volumetric_absorptive_microsampling-_liquid_chromatography_mass_spectrometry_method_for_the_analysis_of_cefepime_in_human_whole_blood:_Application_to_pediatric_pharmacokinetic_study L2 - https://linkinghub.elsevier.com/retrieve/pii/S0731-7085(19)31553-5 DB - PRIME DP - Unbound Medicine ER -