Subcutaneous Absorption Contributes to Observed Interindividual Variability in Adalimumab Serum Concentrations in Crohn's Disease: A Prospective Multicentre Study.
Crohn’s disease
absorption rate
adalimumab
pharmacokinetics
therapeutic drug monitoring
Journal
Journal of Crohn's & colitis
ISSN: 1876-4479
Titre abrégé: J Crohns Colitis
Pays: England
ID NLM: 101318676
Informations de publication
Date de publication:
27 Sep 2019
27 Sep 2019
Historique:
pubmed:
2
3
2019
medline:
25
2
2020
entrez:
2
3
2019
Statut:
ppublish
Résumé
Therapeutic drug monitoring is used to optimise adalimumab therapy in patients with Crohn's disease [CD]. However, the interindividual variability in drug absorption and the quantitative effect on drug clearance of anti-adalimumab antibodies [AAA], measured with a drug-resistant assay, are unclear. We aimed to characterise adalimumab population pharmacokinetics [PopPK] and identify determinants of interindividual variability in patients with CD. In a prospective multicentre open-label cohort study in 28 patients with CD starting adalimumab therapy peak, intermediate, and trough serum samples were analysed for adalimumab and AAA concentrations using a drug resistant assay. Adalimumab concentration-time data were analysed by non-linear mixed effects modelling and were adequately described by a PopPK model with first-order absorption and one-compartment disposition with linear elimination. Clinical remission at Week 12 [W12] was defined as a Harvey-Bradshaw index ≤4. The absorption rate, volume of distribution, and clearance estimates of a typical patient were respectively 0.343 /day, 7.8 L, and 0.330 L/day. A 4-fold difference in the range of adalimumab concentrations was observed 7 days after the first dose and found to be inversely correlated with baseline lean body weight [LBW], soluble tumour necrosis factor [s-TNF], and s-TNF receptor-1 whereas positive AAA and higher LBW were found to be important predictors of accelerated clearance. An adalimumab concentration at W12 of >7.3 µg/mL was significantly associated with achieving clinical remission at W12. Variability in subcutaneous drug absorption is an important contributor to the observed interindividual variability in adalimumab concentrations, in addition to drug clearance [ClinicalTrials.gov NCT02450513].
Sections du résumé
BACKGROUND AND AIM
OBJECTIVE
Therapeutic drug monitoring is used to optimise adalimumab therapy in patients with Crohn's disease [CD]. However, the interindividual variability in drug absorption and the quantitative effect on drug clearance of anti-adalimumab antibodies [AAA], measured with a drug-resistant assay, are unclear. We aimed to characterise adalimumab population pharmacokinetics [PopPK] and identify determinants of interindividual variability in patients with CD.
METHODS
METHODS
In a prospective multicentre open-label cohort study in 28 patients with CD starting adalimumab therapy peak, intermediate, and trough serum samples were analysed for adalimumab and AAA concentrations using a drug resistant assay. Adalimumab concentration-time data were analysed by non-linear mixed effects modelling and were adequately described by a PopPK model with first-order absorption and one-compartment disposition with linear elimination. Clinical remission at Week 12 [W12] was defined as a Harvey-Bradshaw index ≤4.
RESULTS
RESULTS
The absorption rate, volume of distribution, and clearance estimates of a typical patient were respectively 0.343 /day, 7.8 L, and 0.330 L/day. A 4-fold difference in the range of adalimumab concentrations was observed 7 days after the first dose and found to be inversely correlated with baseline lean body weight [LBW], soluble tumour necrosis factor [s-TNF], and s-TNF receptor-1 whereas positive AAA and higher LBW were found to be important predictors of accelerated clearance. An adalimumab concentration at W12 of >7.3 µg/mL was significantly associated with achieving clinical remission at W12.
CONCLUSION
CONCLUSIONS
Variability in subcutaneous drug absorption is an important contributor to the observed interindividual variability in adalimumab concentrations, in addition to drug clearance [ClinicalTrials.gov NCT02450513].
Identifiants
pubmed: 30820530
pii: 5367295
doi: 10.1093/ecco-jcc/jjz050
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Adalimumab
FYS6T7F842
Banques de données
ClinicalTrials.gov
['NCT02450513']
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
1248-1256Informations de copyright
Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.