Niels Vande Casteele1,2, Filip Baert3, Sumin Bian1, Erwin Dreesen1, Griet Compernolle1, Gert Van Assche4,5, Marc Ferrante4,5, Severine Vermeire4,5, Ann Gils1. 1. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 2. Department of Medicine, University of California San Diego, La Jolla, CA, USA. 3. Department of Gastroenterology, AZ Delta, Roeselare, Belgium. 4. Translational Research in GastroIntestinal Disorders [TARGID], KU Leuven, Leuven, Belgium. 5. Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
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].
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].
Authors: Aysha H Al-Ani; Ralley E Prentice; Clarissa A Rentsch; Doug Johnson; Zaid Ardalan; Neel Heerasing; Mayur Garg; Sian Campbell; Joe Sasadeusz; Finlay A Macrae; Siew C Ng; David T Rubin; Britt Christensen Journal: Aliment Pharmacol Ther Date: 2020-05-26 Impact factor: 9.524
Authors: Niels Vande Casteele; Brian G Feagan; Douglas C Wolf; Anca Pop; Mohamed Yassine; Sara N Horst; Timothy E Ritter; William J Sandborn Journal: Inflamm Bowel Dis Date: 2021-07-27 Impact factor: 5.325