Development and validation of a methotrexate adherence assay.
Aged
Antirheumatic Agents
/ administration & dosage
Arthritis, Rheumatoid
/ drug therapy
Chromatography, High Pressure Liquid
/ methods
Dose-Response Relationship, Drug
Female
Humans
Male
Mass Spectrometry
/ methods
Medication Adherence
Methotrexate
/ administration & dosage
Middle Aged
Reproducibility of Results
adherence
assay
methotrexate
pharmacokinetic
rheumatoid arthritis
Journal
Annals of the rheumatic diseases
ISSN: 1468-2060
Titre abrégé: Ann Rheum Dis
Pays: England
ID NLM: 0372355
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
29
03
2019
revised:
02
05
2019
accepted:
06
05
2019
pubmed:
7
6
2019
medline:
1
4
2020
entrez:
7
6
2019
Statut:
ppublish
Résumé
The first-line therapy for rheumatoid arthritis (RA) is weekly oral methotrexate (MTX) at low dosages (7.5-25 mg/week). However, ~40% of patients are non-adherent which may explain why some do not respond and need to start more expensive biological therapies. To monitor adherence more accurately and develop strategies to improve it, a validated objective MTX adherence test is required. To develop and validate the diagnostic accuracy of a novel MTX adherence assay using high-performance liquid chromatography-selected reaction monitoring- mass spectrometry (HPLC-SRM-MS) based biochemical analysis of drug levels. 20 patients with RA underwent MTX pharmacokinetic assessment using HPLC-SRM-MS MTX plasma concentration analysis over a 6-day period. Directly observed therapy was the reference standard. Pharmacokinetic model validation was performed using independent plasma samples from real-world patients (n=50) with self-reported times of drug administration. Following assay optimisation, the sensitivity of the assay to detect adherence was established using samples from an observational cohort study (n=138). A two-compartment pharmacokinetic model was developed and validated. Simulations described the sensitivity required for MTX detection over 7 days; subsequent assay optimisation and retesting of samples confirmed that all patients were correctly identified as MTX adherers. Using real-world samples, the assays sensitivity was 95%. Non-adherence to MTX is common and can have a significant effect on disease activity. HPLC-SRM-MS plasma analysis accurately detects MTX adherence. The validated objective test could easily be used in clinic to identify patients requiring adherence support.
Sections du résumé
BACKGROUND
The first-line therapy for rheumatoid arthritis (RA) is weekly oral methotrexate (MTX) at low dosages (7.5-25 mg/week). However, ~40% of patients are non-adherent which may explain why some do not respond and need to start more expensive biological therapies. To monitor adherence more accurately and develop strategies to improve it, a validated objective MTX adherence test is required.
OBJECTIVE
To develop and validate the diagnostic accuracy of a novel MTX adherence assay using high-performance liquid chromatography-selected reaction monitoring- mass spectrometry (HPLC-SRM-MS) based biochemical analysis of drug levels.
METHODS
20 patients with RA underwent MTX pharmacokinetic assessment using HPLC-SRM-MS MTX plasma concentration analysis over a 6-day period. Directly observed therapy was the reference standard. Pharmacokinetic model validation was performed using independent plasma samples from real-world patients (n=50) with self-reported times of drug administration. Following assay optimisation, the sensitivity of the assay to detect adherence was established using samples from an observational cohort study (n=138).
RESULTS
A two-compartment pharmacokinetic model was developed and validated. Simulations described the sensitivity required for MTX detection over 7 days; subsequent assay optimisation and retesting of samples confirmed that all patients were correctly identified as MTX adherers. Using real-world samples, the assays sensitivity was 95%.
CONCLUSION
Non-adherence to MTX is common and can have a significant effect on disease activity. HPLC-SRM-MS plasma analysis accurately detects MTX adherence. The validated objective test could easily be used in clinic to identify patients requiring adherence support.
Identifiants
pubmed: 31167761
pii: annrheumdis-2019-215446
doi: 10.1136/annrheumdis-2019-215446
pmc: PMC6788879
doi:
Substances chimiques
Antirheumatic Agents
0
Methotrexate
YL5FZ2Y5U1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1192-1197Subventions
Organisme : Medical Research Council
ID : G1000417
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N00583X/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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