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Quantitative determination of lurbinectedin, its unbound fraction and its metabolites in human plasma utilizing ultra-performance LC-MS/MS.
King, Nicholas; Garcia-Martinez, Soledad; Alcaraz, Eider; Grisalena, Alba; Lubomirov, Rubin; Altares, Raquel; Fernandez-Teruel, Carlos; Francesch, Andrés M; Avilés, Pablo M; Fudio, Salvador.
Afiliação
  • King N; Dynakin S.L. Bioanalytical Laboratory, Derio, Spain.
  • Garcia-Martinez S; Dynakin S.L. Bioanalytical Laboratory, Derio, Spain.
  • Alcaraz E; Dynakin S.L. Bioanalytical Laboratory, Derio, Spain.
  • Grisalena A; Dynakin S.L. Bioanalytical Laboratory, Derio, Spain.
  • Lubomirov R; PharmaMar S.A., Clinical Development, Colmenar Viejo (Madrid), Spain.
  • Altares R; PharmaMar S.A., Clinical Development, Colmenar Viejo (Madrid), Spain.
  • Fernandez-Teruel C; PharmaMar S.A., Clinical Development, Colmenar Viejo (Madrid), Spain.
  • Francesch AM; PharmaMar S.A., Research and Development, Colmenar Viejo (Madrid), Spain.
  • Avilés PM; PharmaMar S.A., Research and Development, Colmenar Viejo (Madrid), Spain.
  • Fudio S; PharmaMar S.A., Clinical Development, Colmenar Viejo (Madrid), Spain.
PLoS One ; 18(3): e0283783, 2023.
Article em En | MEDLINE | ID: mdl-36996147
ABSTRACT

AIMS:

Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods to quantify total lurbinectedin, its plasma protein binding to derive the unbound fraction and its main metabolites 1',3'-dihydroxy-lurbinectedin (M4) and N-desmethyl-lurbinectedin (M6) in human plasma, were developed and validated. MATERIALS &

METHODS:

For lurbinectedin, sample extraction was performed using supported liquid extraction. For metabolites, liquid-liquid extraction with stable isotope-labeled analogue internal standards was used. Plasma protein binding was evaluated using rapid equilibrium dialysis. In vitro investigations at different plasma protein concentrations were carried out to estimate dissociation rate constants to albumin and alpha-1-acid glycoprotein (AAG).

RESULTS:

Calibration curves displayed good linearity over 0.1 to 50 ng/mL for lurbinectedin and 0.5 to 20 ng/mL for the metabolites. Methods were validated in accordance with established guidance. The inter-day precision and accuracy ranged from 5.1% to 10.7%, and from -5% to 6% (lurbinectedin in plasma); from 3.1% to 6.6%, and from 4% to 6% (lurbinectedin in plasmaPBS); from 4.5% to 12.9%, and from 4% to 9% (M4); and from 7.5% to 10.5%, and from 6% to 12% (M6). All methods displayed good linearity (r2 >0.99). Recovery was evaluated for lurbinectedin in plasmaPBS (66.4% to 86.6%), M4 (7.82% to 13.4%) and M6 (22.2% to 34.3%). The method for lurbinectedin in plasma has been applied in most clinical studies, while the plasmaPBS and metabolites methods were used to evaluate the impact of special conditions on lurbinectedin PK. Lurbinectedin plasma protein binding was 99.6% and highly affected by AAG concentration.

CONCLUSIONS:

These UPLC-MS/MS methods enable the rapid and sensitive quantification of lurbinectedin and its main metabolites in clinical samples.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carbolinas / Espectrometria de Massas em Tandem Tipo de estudo: Guideline Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carbolinas / Espectrometria de Massas em Tandem Tipo de estudo: Guideline Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article