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Subcutaneous Absorption Contributes to Observed Interindividual Variability in Adalimumab Serum Concentrations in Crohn’s Disease: A Prospective Multicentre Study

Published on Sep 27, 2019in Journal of Crohns & Colitis
· DOI :10.1093/ecco-jcc/jjz050
Niels Vande Casteele24
Estimated H-index: 24
(UCSD: University of California, San Diego),
Filip Baert38
Estimated H-index: 38
+ 6 AuthorsAnn Gils38
Estimated H-index: 38
(Katholieke Universiteit Leuven)
Abstract
BACKGROUND AND AIM: 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: 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: 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: 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].
  • References (42)
  • Citations (6)
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References42
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BACKGROUND AND AIMS: Therapeutic drug monitoring [TDM] has proven to be effective for optimising anti-tumour necrosis factor [TNF] therapy in inflammatory bowel disease [IBD]. Nevertheless, the majority of data refer to infliximab and reactive testing or association studies. We aimed to compare the long-term outcome of patients with IBD who received at least one proactive TDM of adalimumab, with standard of care, defined as empirical dose escalation and/or reactive TDM. METHODS: This was a multi...
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