Development and validation of a bioanalytical method based on LC-MS/MS analysis for the quantitation of CIGB-814 peptide in plasma from Rheumatoid Arthritis patients
| Autor: | Ania Cabrales-Rico, Luis Javier González, Yassel Ramos, Yusimi Reyes, Hilda Garay, Osmel García, Yordanka Masforrol, Ana Marta López, Vladimir Besada, María Domínguez, Noraylis Lorenzo, Jorge Alexis, Dinhora Prada |
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| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
Bioanalysis Clinical Biochemistry Cmax Pharmaceutical Science Peptide Pharmacology 01 natural sciences Epitope Analytical Chemistry Arthritis Rheumatoid 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Liquid chromatography–mass spectrometry Tandem Mass Spectrometry Drug Discovery medicine Humans Peptide sequence Spectroscopy 030203 arthritis & rheumatology chemistry.chemical_classification 010401 analytical chemistry medicine.disease 0104 chemical sciences chemistry Rheumatoid arthritis Peptides Chromatography Liquid |
| Zdroj: | Journal of pharmaceutical and biomedical analysis. 143 |
| ISSN: | 1873-264X |
| Popis: | CIGB-814, originally named as E18-3 APL1 or APL1 in preclinical experiments, is a novel therapeutic peptide candidate for Rheumatoid Arthritis (RA). It is an altered peptide ligand containing a novel CD4+ T-cell epitope of human heat shock protein 60 (83-109, MW 2988.38g/mol) with a mutation (D100→L) that increases its affinity for HLA-II type molecules associated to RA. A bioanalytical method, based on LC-MS/MS analysis, in the SRM mode was developed and fully validated to quantify this peptide in human plasma. An internal standard with the same amino acid sequence but labeled with three (13C615N2)-Lys residues was used for quantitation. The method provides a linear range from 1.5 to 48ng/mL (without matrix effect and carry over) and an accuracy and precision good enough for monitoring more than 80% of the AUC of the PK profile in a phase I clinical trial. The peptide was administered subcutaneously in three dose levels (1, 2.5 and 5mg) not normalized to the body weight of patients with RA. The low doses imposed an analytical challenge; however, a LLOQ of 1.5ng/mL enabled the PK analysis. The Cmax, reached at 0.5h, showed a great variability, that was most likely due to the non-normalized doses; the proposed mechanism for this peptide; and the variability between patients. A rapid clearance of this peptide (4-6h) is advantageous for an immunomodulatory drug, because the therapeutic schedule requires repeated dosages to restore peripheral tolerance. |
| Databáze: | OpenAIRE |
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