Characterizing effect of methotrexate on adalimumab PK in pediatric patients with inflammatory rheumatic disease
Klervi Golhen1*, Tatjana Welzel1,2,3*, Andrew Atkinson1, Verena Gotta1, Jasmin Kuemmerle-Deschner2, Gilbert Koch1, Johannes van den Anker1, Andreas Woerner2*, Marc Pfister1*
1Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel (UKBB), University of Basel, Basel, Switzerland 2Pediatric Rheumatology, University Children’s Hospital Basel (UKBB), University of Basel, Basel, Switzerland 3Pediatric Rheumatology and Autoinflammation reference Center Tuebingen (arcT), University Children`s Hospital Tuebingen, University of Tuebingen, Tuebingen, Germany
Introduction/Objectives:
Adalimumab is a monoclonal antibody directed against tumor necrosis factor alpha (TNF-alpha), used for treatment of various inflammatory diseases, including pediatric inflammatory rheumatic diseases (PiRD). In PiRD patients, adalimumab is administered as fixed dose for approved weight bands every other week. Concomitant treatment and maturational processes are currently not taken into account. Whereas in some indications target Cmin (“trough”) values associated with improved response and reduced risk of immunogenicity have been defined, no target values for adalimumab exist for PiRD patients. This pharmacometric analysis aims to characterize magnitude of effect of concomitant methotrexate (MTX) treatment, disease activity, and other factors on the pharmacokinetics (PK) of adalimumab in PiRD patients.
Methods:
Data originates from a multi-center prospective observational study (NCT04042792) in PiRD patients aged 2-18 years, treated with adalimumab and MTX (group 1, n=14) or adalimumab alone (group 2, n=14) for ≥ 12 weeks (“adalimumab steady-state cohort”). For each study patient, adalimumab concentrations were measured 1-9 days (“peak”) and 10-14 days (“trough”) during clinical routine following adalimumab administration during 3-6 months of treatment. Data was combined with a third group of PiRD patients (group 3 “adalimumab naïve cohort”, n=5 treated with adalimumab and MTX and n=3 treated with adalimumab) providing additional “peak” (3-7 days) after first adalimumab dose and/or “trough” concentrations after the first adalimumab dose. Adalimumab concentrations were measured with an enzyme-linked immunosorbent assay (EIA, lower limit of quantification LLOQ: 0.5 µg/mL). A pharmacometric (PMX) pharmacokinetic analysis was performed utilizing MONOLIX (V.2020 R1). The following covariates were investigated on adalimumab clearance: baseline weight versus BSA (allometric scaling/power), MTX presence/absence, first MTX dose (relationships according to graphical assessment), disease severity (last C-reactive protein (CRP) versus erythrocyte sedimentation rate (ESR) versus juvenile arthritis disease assessment score (JADAS-10) before PK measurement, relationships according to graphical assessment); if significant: CRP, ESR, JADAS-10, MTX dose as regressors; if a relationship is suggested graphically: baseline age and duration of adalimumab at PK measurement. Body weight (WT) was included in the PK parameters following an allometric relationship. Key inflammatory parameters as well as disease activity were scored using physician global assessment score (PGA), parent/patient global assessment score (PPGA) and JADAS-10 at each study visit.
Results:
A total of 36 patients (21 female) were included in PMX analysis; 25 were diagnosed with juvenile idiopathic arthritis (JIA), 10 with idiopathic uveitis, and 1 with chronic recurrent multifocal osteomyelitis (CRMO). A total of 72 serum adalimumab concentrations (no LLOQ) were measured (median: 10.5 µg/mL, range: 0.5-17.3 µg/mL). Applying standard weight-based allometric scaling, a simple one compartment model with first order absorption (Ka fixed to 0.2/day [1]) and elimination adequately described available adalimumab concentration-time data. No relevant effect of MTX on apparent clearance (CL/F) of adalimumab could be found as CL/F was estimated to be reduced by 15% if co-administered with MTX. Among other clinical variables analyzed, duration of adalimumab treatment was associated with significant increase in CL/F.
Conclusions:
This is the first post-marketing authorisation PMX analysis of adalimumab PK in PiRD patients. As opposed to data in the Humira - Extension of indication variation assessment report published by EMA in 2020, effect of MTX on adalimumab clearance was marginal while confirming previous reports of increasing adalimumab clearance over time [2]. This is potentially caused by target saturation due to excess of adalimumab at high clinical doses. Longer exposition to adalimumab is linked to increase in drug clearance, indicating a potential tolerance mechanism or the presence of neutralizing anti-drug antibodies. Individualized dosing strategies with model-based simulations will further enhance efficacy-safety balance of adalimumab in PiRD patients.
References:
[1] Sharma S, et al. Inflamm Bowel Dis 2015
[2] Marquez et al. Pharmaceutics 2021