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Quantification of Efavirenz Hydroxymetabolites in Human Plasma Using LC-HRMS/MS.
Pettersson Bergstrand, Madeleine; Soeria-Atmadja, Sandra; Barclay, Victoria; Tolic, Jelena; Navér, Lars; Gustafsson, Lars L; Pohanka, Anton.
Afiliação
  • Pettersson Bergstrand M; Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
  • Soeria-Atmadja S; Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Barclay V; Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; and.
  • Tolic J; Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
  • Navér L; Department of Clinical Pharmacology, Karolinska University Hospital, 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.
Ther Drug Monit ; 46(4): 468-476, 2024 Aug 01.
Article em En | MEDLINE | ID: mdl-38864581
ABSTRACT

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 ß-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.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Ciclopropanos / Benzoxazinas / Alcinos / Espectrometria de Massas em Tandem Limite: Child / Child, preschool / Humans Idioma: En Revista: Ther Drug Monit Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Suécia

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Ciclopropanos / Benzoxazinas / Alcinos / Espectrometria de Massas em Tandem Limite: Child / Child, preschool / Humans Idioma: En Revista: Ther Drug Monit Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Suécia