POS0017 SUCCESSFUL THERAPEUTIC DRUG MONITORING BASED ADALIMUMAB DOSE REDUCTION IN RHEUMATOID ARTHRITIS PATIENT WITH LOW DISEASE ACTIVITY (ADDORA-LOW): A SINGLE BLIND, NON-INFERIORITY, RANDOMIZED CLINICAL TRIAL
Authors: S. Atiqi, M. H. M. Wientjes, M. Leeuw, L. Boekel, F. Hooijberg, F. Loeff, C. Krieckaert, A. De Vries, M. Nurmohamed, T. Rispens, M. Boers, B. Van den Bemt, A. A. Den Broeder, G. J. Wolbink
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> The latest European and American recommendations support tapering of biological DMARDs (bDMARDs) in patients with persistent remission or low disease activity. Most clinicians use disease activity scores to monitor dose tapering. Considering the inter-individual variation in serum concentration of biologics, this trial-and-error approach is inevitably associated with increased risk of flare. Dose tapering of bDMARDs in patients with low serum concentrations could lead to too low and consequently to ineffective serum concentrations and flares. There is compelling evidence that withdrawal of bDMARDs will lead to flares. A novel approach would be a tailored tapering strategy based on assessment of serum concentration, i.e., therapeutic drug monitoring (TDM). The concentration effect curve of adalimumab (ADA) suggests that patient with concentration higher than 5mg/L have a higher chance of being overexposed [1]. In the first phase of treatment, an ADA concentration of 5 mg/L is probably needed to achieve adequate clinical response. However, to control disease activity after 28 weeks, lower concentrations are probably sufficient. To date, a study employing a TDM-based tapering strategy to define the lowest effective drug level has not been done. <h3>Objectives:</h3> In rheumatoid arthritis (RA) patients with low disease activity after &gt;28 weeks of ADA treatment, we assessed whether a strategy using TDM-based dose adjustments to a target concentration of 2 mg/L was non-inferior to that with a concentration of 5 mg/L with respect to disease activity. Secondarily, superiority in reducing the amount of drug administered was assessed between both groups. <h3>Methods:</h3> The ADDORA-low study, a randomized, single blinded, non-inferiority clinical trial, enrolled 62 RA patients on ongoing ADA therapy (40 mg every other week) for at least 28 weeks, with low disease activity and an ADA concentration of &gt; 5 mg/L. Patients were randomly 1:1 assigned to dose reduction aiming a serum drug level of either 2 mg/L or 5 mg/L. The newly developed algorithm based on the PK/PD model of Ternant [2] determined the dosing interval to achieve the target drug level. Clinical visits were scheduled at baseline (prior to dose reduction), 12 weeks and 24 weeks thereafter. The primary endpoint was the mean time weighted DAS28-CRP (MTW-DAS28) after 24 weeks. Noninferiority was defined as a difference with an upper 95%CI no greater than 0.6. Secondary outcomes included number of flares and ADA dosing, expressed as number of injections used during 24 weeks. <h3>Results:</h3> Randomization created similar study groups (Table 1). The mean ADA concentration decreased from 10.1 mg/L (SD 3.5) to 5.6 mg/L (3.0) and from 9.9 mg/L (3.8) to 3.3 mg/L (1.4) respectively for the 5 mg/L and 2 mg/L group (Figure 1A). The MTW-DAS28 at week 24 was 0.23 lower in the 2mg/L group [95%CI –0.07;0.53] P=0.14. The odds of having a flare was 1,30 higher in the 2mg/L group, which was a nonsignificant difference (OR 1.30 [95%CI 0.31;5.38] P=0.72). The total number of injections over 24 weeks was significantly lower in 2mg/L group: 30% difference (2 [95%CI –1,31; –2.85} P&lt; 0.001) (Figure 1C). <h3>Conclusion:</h3> TDM-based tapering strategy targeting a drug level of 2 mg/L is non-inferior to a target level of 5 mg/L with respect to disease activity and number of flares, while it saves a significant amount of medication. This in turn reduces patients' burden of self-injections, potential risk of adverse events and costs, making this a more personalized, safe and effective strategy. <b>Table 1.</b> Baseline characteristics <h3>REFERENCES:</h3> [1] Pouw MF, Krieckaert CL, Nurmohamed MT, van der Kleij D, Aarden L, Rispens T, et al. Key findings towards optimising adalimumab treatment: the concentration–effect curve. Annals of the Rheumatic Diseases. 2015;74(3):513-8. [2] Ternant D, Ducourau E, Fuzibet P, Vignault C, Watier H, Lequerré T, et al. Pharmacokinetics and concentration–effect relationship of adalimumab in rheumatoid arthritis. British Journal of Clinical Pharmacology. 2015;79(2):286-97. <h3>Acknowledgements:</h3> All participating patients, all medical doctors and nurses of Reade and Sint Maartenskliniek, ADDORA team of Reade and Sint Maartenskliniek, ZonMw. <h3>Disclosure of Interests:</h3> <b>None declared.</b>