Quantification of Efavirenz Hydroxymetabolites in Human Plasma Using LC-HRMS/MS.

T genotype and perturbed blood-brain barrier due to tuberculous meningitis. Antimicrob Agents Chemother. 2016;60:4511–4518.
Soeria-Atmadja S, Amuge P, Nanzigu S, et al. Pretreatment HIV drug resistance predicts accumulation of new mutations in ART-naive Ugandan children. Acta Paediatr. 2020;109:2706–2716.
EMA. Guideline on Bioanalytical Method Validation . 2011; EMEA/CHMP/EWP/192217/2009 rev. 1 corr. 2**. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf .
Matuszewski BK, Constanzer ML, Chavez-Eng CM. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Anal Chem. 2003;75:3019–3030.
EU. Commission Implementing Regulation (EU) 2021/808 of 22 March 2021 on the Performance of Analytical Methods for Residues of Pharmacologically Active Substances Used in Food-Producing Animals and on the Interpretation of Results as Well as on the Methods to be Used for Sampling and Repealing Decisions 2002/657/EC and 98/179/EC. Available at: https://eur-lex.europa.eu/eli/reg_impl/2021/808/oj .
FDA. CVM GFI#118 Mass Spectrometry for Confirmation of Identity of Animal Drug Residues. 2003.
FDA. Acceptance Criteria for Confirmation of Identity of Chemical Residues Using Exact Mass Data for the FDA Foods and Veterinary Medicine Program. 2015.
Maurin MB, Rowe SM, Blom K, et al. Kinetics and mechanism of hydrolysis of efavirenz. Pharm Res. 2002;19:517–521.
Rao RN, Ramachandra B, Vali RM, et al. LC-MS/MS studies of ritonavir and its forced degradation products. J Pharm Biomed Anal. 2010;53:833–842.
Deng Y, Liu R, Yang P, et al. Rapid identification of efavirenz metabolites in rats and humans by ultra high performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry. J Sep Sci. 2015;38:1529–1536.
Vermeir M, Lachau-Durand S, Mannens G, et al. Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects. Drug Metab Dispos. 2009;37:809–820. -->
Grant Information: ALF project 20170343 Stockholms Läns Landsting; 2011-3440 Vetenskapsrådet; VR-Link 2012-3466 Vetenskapsrådet
Substance Nomenclature: 0 (Cyclopropanes)
0 (Benzoxazines)
0 (Alkynes)
JE6H2O27P8 (efavirenz)
0 (Anti-HIV Agents)
P8S49CKH6L (8-hydroxyefavirenz)
Entry Date(s): Date Created: 20240612 Date Completed: 20240711 Latest Revision: 20240711
Update Code: 20240711
DOI: 10.1097/FTD.0000000000001173
PMID: 38864581
Autor: Pettersson Bergstrand M; Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.; Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden., Soeria-Atmadja S; Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; and.; Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden., Barclay V; Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.; Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden., Tolic J; Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden., Navér L; Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; and.; Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden., Gustafsson LL; Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden., Pohanka A; Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.; Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: Therapeutic drug monitoring [Ther Drug Monit] 2024 Aug 01; Vol. 46 (4), pp. 468-476. Date of Electronic Publication: 2024 Jun 11.
DOI: 10.1097/FTD.0000000000001173
Abstrakt: Background: Efavirenz (EFV) is a drug used to treat HIV. Low plasma concentrations of EFV result in suboptimal viral suppression, whereas high concentrations can cause adverse neuropsychiatric side reactions. Some studies have identified a correlation between the plasma concentrations of EFV metabolites and neurotoxicity. To our knowledge, no studies have investigated the metabolism of EFV in young children and its effect on treatment outcomes. Therefore, the aim of this study was to develop and validate a method for quantifying EFV and its metabolites in human plasma derived from children.
Methods: Sample preparation was performed using protein precipitation of 100 µL plasma. Thereafter, an aliquot of the supernatant was used to quantify EFV, 7-hydroxyefavirenz (7-OH-EFV), 8-hydroxyefavirenz (8-OH-EFV), and a newly discovered metabolite ("EFAdeg") associated with 8-OH-EFV. A second aliquot of the supernatant was hydrolyzed using β-glucuronidase/arylsulfatase and used with the first aliquot to quantify phase II metabolites. The analyses were performed using a Dionex Ultimate 3000RS LC-system coupled with a Q Exactive Orbitrap mass spectrometer.
Results: The method has a measuring range of 100-50,000 ng/mL (EFV, 8-OH-EFV), 125-25,000 ng/mL (7-OH-EFV), and 200-10,000 ng/mL ("EFAdeg"). All criteria of the European Medicines Agency guidelines regarding precision, accuracy, and selectivity were met. Of note, carryover must be considered for 8-OH-EFV. Overall, the validated method was successfully applied to plasma samples obtained from children and confirmed the presence of the newly discovered metabolite, "EFAdeg."
Conclusions: An LC-HRMS/MS method for the quantification of EFV and its phase I and II metabolites was developed and validated. This method is suitable for analyzing plasma samples from children. Furthermore, studies using this method identified an additional metabolite that may influence the concentration of 8-OH-EFV in patient samples.
Competing Interests: The authors declare no conflict of interest.
(Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: