Topics

Adalimumab Dose Reduction Aiming Low Serum Concentration With Control of Disease Activity

2020-01-15 10:26:57 | BioPortfolio

Summary

Several prior studies have shown that dose reduction or discontinuation of tumor necrosis factor (TNF)-inhibitors, like adalimumab, is possible in substantial number of patients with a rheumatic disease without an increase in disease activity. Prior studies showed that patients with concentrations higher than 5 mg/L are overexposed to adalimumab and can safely reduce the dose. In the first phase of treatment, an adalimumab concentration of 5mg/L is needed to achieve adequate clinical response. However to control disease activity after 28 weeks, lower concentration than 5 mg/L are probably sufficient. Recent published data suggest that concentrations of 0.1-0.5 mg/L are enough to control TNF blockade in this state. Yet, a study which investigates the lowest effective drug serum concentration is missing so far. The hypothesis is that serum adalimumab concentration of 2 mg/L is sufficient to control disease activity.

Description

Biological agents are frequently prescribed to optimize rheumatoid arthritis care. In order to prevent joint destruction it is necessary to maintain remission or low disease activity. Up to now clinicians used to continue the initial treatment regimen to maintain remission or low disease activity. Since biologic therapy is expensive, and is associated with patient burden as dose dependant risk for serious infections, multiple studies have been performed to show that a large proportion of patients with rheumatoid arthritis with stable low disease activity can reduce their dose without relapse of disease. In addition the latest European and American recommendations pose to reduce the dosage or to discontinue the bDMARDs in case of persistent remission or low disease activity. Yet, there are no recommendations on how this should be carried out.

Currently, most clinicians use Disease Activity Score in 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI) to monitor dose reduction strategies. Although disease activity guided dose reduction is safe and cost-effective, a relatively novel strategy is dose reduction using serum drug concentrations (therapeutic drug monitoring). Most biologics are characterized by wide variation in pharmacokinetics between patients, resulting in wide range of drug concentrations when administered at the labeled dose. Therapeutic drug monitoring can be a valuable tool for optimizing the dosage of biopharmaceuticals and improving patient care on individual level. In other autoimmune diseases, such as inflammatory bowel disease, it is thought to be superior to empirical dose reduction and is already applied in clinical practice.

The rationale behind therapeutic drug monitoring is that medication dose correlates with serum drug levels and drug concentration correlates with therapeutic effect. The latter notion is demonstrated for adalimumb by Pouw et al. Adalimumab serum concentration in a range 5-8 mg/L is sufficient for adequate response. In the first phase of treatment, drug concentration must be high enough to control immunogenicity. To control disease activity in the 2nd phase (after 28 weeks), lower concentrations than 5 mg/L are probably sufficient. Our study group illustrated in 2018 that reducing adalimumab dose by prolonging the dosing interval with 50%, is non-inferior to continuation in patients with adalimumab levels > 8mg/L. In addition, recent published data suggest that concentrations of 0.1-0.5 mg/L are enough to control TNF in this phase. Since around 70% of the patients have adalimumab concentration above 5 mg/l, while an adalimumab concentration of 5 mg/L is enough for adequate response (7), a large extent of patients might thus be overexposed.

The hypothesis is that 1/ tapering adalimumab in RA patient doing well after 28 weeks using TDM aiming at 5mg/l (and disease activity measurement) results in maintenance of disease control and lower adalimumab use, and that 2/ tapering to a lower target drug level of 2 mg/L is non inferior to the higher 5mg/l target with respect to disease activity control and safety, and superior in adalimumab reduction. Tapering to achieve these lower targets (for example direct doubling of interval in patients with levels > 10 mg/L) might result in the lowest effective drug dose.

Disease activity after dose reduction, aiming adalimumab concentration of 2 mg/L or 5 mg/L, in rheumatoid arthritis patients treated with adalimumab for at least 28 weeks and a serum adalimumab concentration above 5 mg/L, will be evaluated in this multi-centre, randomized, single blinded trail. Patients with an adalimumab concentration above 5mg/L will be randomly assigned to dose reduction by extending their dosing interval aiming a drug level of 2 mg/L or aiming a drug level of 5 mg/L. A newly developed algorithm is used to determine the interval prolongation for each patient

Data regarding disease status, functioning, adalimumab serum concentrations, anti-drug antibodies and medical costs will be collected during this study.

Study Design

Conditions

Rheumatoid Arthritis

Intervention

Dose reduction to 2mg/L, Dose reduction to 5mg/L, Adalimumab

Location

Reade Rheumatology Research Institute
Amsterdam
Noord Holland
Netherlands
1056AB

Status

Recruiting

Source

Reade Rheumatology Research Institute

Results (where available)

View Results

Links

Published on BioPortfolio: 2020-01-15T10:26:57-0500

Clinical Trials [10534 Associated Clinical Trials listed on BioPortfolio]

Adalimumab Drug Optimisation in Rheumatoid Arthritis Using Therapeutic Drug Monitoring

Several prior studies have shown that dose reduction of Tumor Necrosis Factor (TNF)-inhibitors like adalimumab is possible in substantial number of rheumatic disease patients without an in...

Open-Label Steroid Reduction Study of Adalimumab With Methotrexate in Patients With Active Rheumatoid Arthritis

The purpose of the study is to evaluate the clinical efficacy of scheduled versus free reduction of steroid treatment in patients with active RA treated with adalimumab + MTX

A Study of Subjects With Rheumatoid Arthritis Who Are in Clinical Remission to Investigate Patient and Disease Characteristics That Could Help Identify Which Subjects Could Reduce Their Adalimumab Dose Without Flaring

A phase 4, multicenter, randomized, double-blind, parallel-group study in subjects with rheumatoid arthritis who are in stable clinical remission for at least 6 months and on treatment wi...

A Study Comparing ABT-494 to Placebo and to Adalimumab in Subjects With Rheumatoid Arthritis Who Are on a Stable Dose of Methotrexate and Who Have an Inadequate Response to Methotrexate (SELECT-COMPARE)

This is a phase 3, randomized, double-blind study comparing ABT-494 to Placebo and to Adalimumab in subjects with moderately to severely active rheumatoid arthritis who are on a stable bac...

Efficacy and Safety of Adalimumab in Patients With Active Rheumatoid Arthritis Treated Concomitantly With Methotrexate.

The purpose of the study is to assess the safety, immunogenicity and clinical efficacy of adalimumab in combination with methotrexate for patients with rheumatoid arthritis.

PubMed Articles [12584 Associated PubMed Articles listed on BioPortfolio]

Outcomes of dose reduction, withdrawal, and restart of tofacitinib in patients with rheumatoid arthritis: a prospective observational study.

This study was designed to compare outcomes of dose reduction, withdrawal, and continuation of tofacitinib in patients with rheumatoid arthritis (RA) and to examine effectiveness of rescue with an ori...

Real-Life Tolerability and Effectiveness of Adalimumab Biosimilar in Rheumatoid Arthritis: ASPIRE Registry Data.

The TNF-α blocker adalimumab is a well-proven therapy for rheumatoid arthritis (RA). A biosimilar adalimumab (ZRC-3197; Exemptia™), a 'fingerprint match' to reference adalimumab, has been approve...

Optimising Low Dose Methotrexate for Rheumatoid Arthritis - A Review.

Methotrexate at low doses (5-25 mg/week) is first-line therapy for rheumatoid arthritis. However, there is inter- and intra-patient variability in response, with contribution of variability in concent...

Live Zoster Vaccine in Patients with Rheumatoid Arthritis Treated with Tofacitinib with or without Methotrexate, or Adalimumab with Methotrexate.

To explore herpes zoster (HZ) rates, and live zoster vaccine (LZV) safety, in a subset of patients with rheumatoid arthritis (RA) who received LZV before tofacitinib ± methotrexate (MTX), or adalimum...

Patient-reported outcomes for tofacitinib with and without methotrexate, or adalimumab with methotrexate, in rheumatoid arthritis: a phase IIIB/IV trial.

To provide the first direct comparison of patient-reported outcomes (PROs) following treatment with tofacitinib monotherapy versus tofacitinib or adalimumab (ADA) in combination with methotrexate (MTX...

Medical and Biotech [MESH] Definitions

The dose amount of poisonous or toxic substance or dose of ionizing radiation required to kill 50% of the tested population.

A polyethylene-glycolated Fab' fragment of TUMOR NECROSIS FACTOR antibody that binds specifically to TNF-ALPHA and neutralises it in a dose-dependent manner. It also inhibits the production of lipopolysaccharide-induced TNF-ALPHA and IL-1 BETA and is used to treat RHEUMATOID ARTHRITIS and PSORIATIC ARTHRITIS.

A humanized monoclonal antibody that binds specifically to TNF-ALPHA and blocks its interaction with endogenous TNF RECEPTORS to modulate INFLAMMATION. It is used in the treatment of RHEUMATOID ARTHRITIS; PSORIATIC ARTHRITIS; CROHN'S DISEASE and ULCERATIVE COLITIS.

Arthritis in children, with onset before 16 years of age. The terms juvenile rheumatoid arthritis (JRA) and juvenile idiopathic arthritis (JIA) refer to classification systems for chronic arthritis in children. Only one subtype of juvenile arthritis (polyarticular-onset, rheumatoid factor-positive) clinically resembles adult rheumatoid arthritis and is considered its childhood equivalent.

A treatment schedule in which the total dose of radiation is divided into large doses.

More From BioPortfolio on "Adalimumab Dose Reduction Aiming Low Serum Concentration With Control of Disease Activity"

Quick Search

Relevant Topics

Cytokine Tumour Necrosis Factor (TNF)
TNF is a compound that is classified as a cytokine which plays a central role in the cellular mechanisms of apoptosis or cell death. However, there are a number of different kinds of TNF, just under twenty, but the family of molecules have very similar a...

Antibodies
An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples of antigens include microorganisms (such as bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produc...


Searches Linking to this Trial