In-depth assessment of the influence of anti-drug antibodies on adalimumab pharmacokinetics and concentration-effect relationship in rheumatoid arthritis
1,2Christophe Passot, 3Theo Rispens, 1,2Gilles Paintaud , 1,4Denis Mulleman, 1,2David Ternant
1CNRS UMR 7292 GICC, Tours, France; 2University of Medicine, Pharmacology and Toxicology Department, Tours, France; 3Sanquin Research, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands; 4University of Medicine, Rheumatology Department, Tours, France;
Objectives: To assess the influence of free and total (free + complexed with adalimumab) anti-adalimumab antibodies on pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic (PK-PD) relationship of adalimumab in rheumatoid arthritis (RA).
Methods: PK and PK-PD data were obtained from a prospective, observational, open, multicentric 26-week study (NCT01382160). Patients received 40 mg adalimumab subcutaneously every other week with or without methotrexate. Adalimumab concentrations and RA disease activity score (DAS28) were measured at inclusion visit, then at weeks 4, 8, 12 and 26. Adalimumab concentrations were measured using a validated enzyme-linked immunosorbent assay [1]. Anti-drug antibodies (ADA) were measured using two assays: Antigen binding test (ABT) and Acid dissociation radioimmunoassay (ARIA) [2], measuring free and both free and adalimumab-complexed ADA, respectively. The PK of adalimumab was described using a one-compartment model with first-order absorption and elimination rates. The relationship between adalimumab concentrations and DAS28 was described using a direct model. Body weight, sex, age and methotrexate cotreatment and ADA measured with both techniques were each tested as covariates on PK and PK-PD parameters. Data were fitted to a PK-PD model using non-linear mixed-effects modelling using Monolix 4.3.3 software (Lixoft).
Results: A total of 251 adalimumab serum trough concentrations and 319 ADA measurements were available in the 66 eligible patients. The following PK and PK-PD parameters were estimated: apparent volume of distribution (Vd/F=9.4 L) and clearance (CL/F=0.38 L/day), and adalimumab concentration leading to 50% decrease of initial DAS28 (C50=16.3 mg/L). Body weight and methotrexate cotreatment respectively increased Vd/F and CL/F. Presence of ADA was strongly associated with increased CL/F, but this association was stronger with free ADA (Δ-2LL=-25) than total ADA (Δ-2LL=-15). The presence of ADA was not associated with altered C50 and therefore seems not to be associated with altered adalimumab potency.
Conclusions: Adalimumab clearance variability is better described using free than total ADA measurement, which corroborates with a previous study showing free ADA as a better predictor of treatment failure than total ADA [3]. In addition, our results suggest that ADA-triggered treatment failure is only due to an alteration of adalimumab pharmacokinetics.
References:
[1] Desvignes C, Edupuganti SR, Darrouzain F, Duveau AC, Loercher A, Paintaud G, Mulleman D. Development and validation of an enzyme-linked immunosorbent assay to measure adalimumab concentration. Bioanalysis. 2015;7(10):1253-60.
[2] Bloem K, van Leeuwen A, Verbeek G, Nurmohamed MT, Wolbink GJ, van der Kleij D, Rispens T. Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients. J Immunol Methods. 2015 Mar;418:29-38.
[3] Van Schouwenburg PA, Krieckaert CL, Rispens T, Aarden L, Wolbink GJ, Wouters D. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding test shows predictive value and transient antibody formation. Ann Rheum Dis. 2013 Oct;72(10):1680-6.