Adalimumab Trough Concentrations Research Articles

Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment

Background Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU.MethodsA retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab.ResultsAdalimumab trough levels were significantly higher in complete responders 11.8 μg/mL (range 6.9–33.0) compared to partial or non-responders 9,2 μg/mL (range 0–13.6) (p = 0,004). Receiver–operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561–0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%).ConclusionsA therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era.

Higher Adalimumab Trough Levels Are Associated with Histologic Remission and Mucosal Healing in Inflammatory Bowel Disease.

(1) Many patients with inflammatory bowel disease (IBD) in endoscopic remission have persistent histologic activity, which is associated with worse outcomes. There are limited data on the association between adalimumab drug concentrations and histologic outcomes using validated histologic indices. We aimed to assess the relationship between adalimumab concentrations and the Robarts Histopathology Index (RHI). (2) Patients from a tertiary IBD center from 2013 to 2020 with serum adalimumab (ADA) trough concentrations measured during maintenance therapy (≥14 weeks) and a colonoscopy or flexible sigmoidoscopy with biopsies performed within 90 days of drug level were included. Blinded histologic scoring using the RHI was performed. Primary analysis assessed the relationship between adalimumab drug concentrations and histologic remission using receiver operating characteristic curve analysis. (3) In 36 patients (26 Crohn's Disease, 9 ulcerative colitis, 1 indeterminate), median adalimumab concentrations were higher (17.3 ug/mL, 12.2-24.0) in patients with histologic remission compared to those without (10.3 ug/mL, 6.8-13.9, p = 0.008). The optimal ADA concentration identified using the Youden threshold was ≥16.3 ug/mL (sensitivity 70%, specificity 90%). Patients with ADA ≥ 16.3 ug/mL had higher histologic remission rates (78%) compared to lower ADA concentrations (14%, p= 0.002), as well as higher mucosal healing rates (86%) compared to lower levels (12%, p = 0.001). Symptoms correlated weakly and non-significantly with both histologic (RHI) scores (r = 0.25, p = 0.2) and adalimumab concentrations (r = 0.05, p = 0.8). (4) The current study demonstrated that higher serum adalimumab concentrations (≥16.3 ug/mL) are needed for histologic remission and mucosal healing assessed using the RHI.

Assessing the Impact of Immunogenicity and Improving Prediction of Trough Concentrations: Population Pharmacokinetic Modeling of Adalimumab in Patients with Crohn's Disease and Ulcerative Colitis.

Predicting adalimumab pharmacokinetics (PK) for patients impacted by anti-drug antibodies (ADA) has been challenging. The present study assessed the performance of the adalimumab immunogenicity assays in predicting which patients with Crohn's disease (CD) and ulcerative colitis (UC) have low adalimumab trough concentrations; and aimed to improve predictive performance of adalimumab population PK (popPK) model in CD and UC patients whose PK was impacted by ADA. Adalimumab PK and immunogenicity data obtained from 1459 patients in SERENE CD (NCT02065570) and SERENE UC (NCT02065622) were analyzed. Adalimumab immunogenicity was assessed using electrochemiluminescence (ECL) and enzyme-linked immunosorbent (ELISA) assays. From these assays, three analytical approaches (ELISA concentrations, titer, and signal-to-noise [S/N] measurements) were tested as predictors for classifying patients with/without low concentrations potentially affected by immunogenicity. The performance of different thresholds for these analytical procedures was assessed using receiver operating characteristic curves and precision-recall curves. Based on the results from the most sensitive immunogenicity analytical procedure, patients were classified into PK-not-ADA-impacted and PK-ADA-impacted subpopulations. Stepwise popPK modeling was implemented to fit the PK data to an empirical adalimumab two-compartment model with linear elimination and ADA delay compartments to account for the time delay to generate ADA. Model performance was assessed by visual predictive checks and goodness-of-fit plots. The classical ELISA-based classification (with 20ng/mL ADA as lower threshold) showed a good balance of precision and recall, to determine which patients had at least 30% adalimumab concentrations below 1µg/mL. Titer-based classification with the lower limit of quantitation (LLOQ) as threshold showed higher sensitivity to classify these patients compared to the ELISA-based approach. Therefore, patients were classified as PK-ADA-impacted or PK-not-ADA impacted using the LLOQ titer threshold. In the stepwise modeling approach ADA-independent parameters were first fit using PK data from titer-PK-not-ADA-impacted population. The identified ADA-independent covariates included the effect of indication, weight, baseline fecal calprotectin, baseline C-reactive protein, baseline albumin on clearance; and sex and weight on volume of distribution of the central compartment. Pharmacokinetic-ADA-driven dynamics were characterized using PK data for the PK-ADA-impacted population. The categorical covariate based on the ELISA classification was the best at describing the additional effect of immunogenicity analytical approaches on ADA synthesis rate. The model was able to adequately describe the central tendency and variability for PK-ADA-impacted CD/UC patients. The ELISA assay was found to be optimal for capturing impact of ADA on PK. The developed adalimumab popPK model is robust in predicting PK profiles for CD and UC patients whose PK was impacted by ADA.

P443 Trough concentration response in infliximab and adalimumab treated children with IBD following treatment adjustment: A pharmacokinetic model

Abstract Background In patients with IBD, data on trough concentration (TC) response to adjustments in anti-TNFα treatment are scarce. Methods We included pediatric patients with IBD who were treated with anti-TNFα agents from, 2015 to, 2020 and had sequential monitoring of TC. Treatment adjustments were detected and subsequent changes in TC were recorded (next infusion for infliximab and up to, 8 weeks TC measurement for adalimumab). Patients with positive anti-drug-antibodies or with concomitant change in immunomodulatory treatment were excluded. Results For the entire cohort (86 patients), median age at diagnosis was, 13.2 (10.7–14.9) years (Females, 48%; Crohn’s disease, 72%). For infliximab, 58 patients had, 201 interval changes (98 decrease and, 103 increase) and, 26 had dose increase. Dose increase resulted in TC change in the same direction but TC changes could not be predicted due to significant variability (p=0.9). This variability could not be attributed to any specific variable. Interval decrease: Median TC pre adjustment was, 4.3 mcg/ml (IQR, 3.1–6.9 mcg/ml). For every, 10% decrease in interval, TC was increased by, 1.6 mcg/ml (B=, 1.6, 95% CI;, 0.9–2.4; p&amp;lt;0.001) or by, 57.2% (B=57.2, 95% CI;12.8–124.6; p=0.014). The presence of perianal disease was associated with attenuated response to interval decrease (diminished TC increase), p=0.001. Interval increase: Median TC pre change was, 12.6 mcg/ml (IQR, 9.5–12.1 mcg/ml). For every, 10% increase in interval, TC was decreased by, 0.66 mcg/ml (B=, 0.66, 95% CI;, 0.2–1.2; p=0.01) or by, 4.2% (B=, 4.2, 95% CI;, 2.0–6.4; p&amp;lt;0.001). The diagnosis of Crohn’s disease (VS. diagnosis of UC) was associated with reduced response to interval increase (diminished TC decrease), p=0.012. For adalimumab, 28 patients had, 31 events of interval decrease from every, 2 weeks to every week and, 12 events of interval increase back to every, 2 weeks. Interval decrease resulted in increased median TC from, 4.5 (3.5–5.3) mcg/ml to, 8.1 (6.5–10.5) mcg/ml (X1.8) while interval increase resulted in TC change from, 15.5 (12.8–18.6) mcg/ml to, 9.7 (6.5–14.6) mcg/ml (:1.6). Changes in adalimumab TC were consistently significant (p&amp;lt;0.001). Increase in delta TC was associated with younger age (p=0.018), lower body surface area (p&amp;lt;0.001) and with the absence of perianal disease (p=0.001). Laboratory measures (CRP, albumin- mostly within normal limits) were not associated with TC response for both agents. Conclusion Changes in TC following treatment adjustment can be almost linearly predicted for adalimumab but not for infliximab. Thus, following infliximab adjustment, TC should be measured in-order to assess adequate TC response.

Association of adalimumab trough concentrations and treatment response in patients with juvenile idiopathic arthritis

To assess the relationship of adalimumab trough concentrations and treatment response in paediatric patients with juvenile idiopathic arthritis (JIA). Monocentric cohort study of JIA patients treated with adalimumab. Clinical data and samples were collected during routine follow-up. Adalimumab trough concentrations were quantified by a novel liquid chromatography-tandem mass spectrometry assay. Anti-adalimumab antibodies were measured in samples with trough concentrations ≤5mg/l. Disease activity was evaluated using the clinical Juvenile Arthritis Disease Activity Score with 71 joint-count (cJADAS71). Response to adalimumab was defined according to recent international treat-to-target guidelines. 35 adalimumab trough samples were available from 34 paediatric patients with JIA. Although there was no significant difference in adalimumab dose, trough concentrations were significantly lower in patients with secondary failure (median 1.0 mg/l; IQR 1.0-5.3) compared with patients with primary failure (median 13.97 mg/l; IQR 11.81-16.67) or an adequate response (median 14.94 mg/l; IQR 10.31-16.19) to adalimumab. Adalimumab trough concentrations were significantly lower in JIA patients with secondary failure compared with patients with primary failure or an adequate response to adalimumab. Results suggest that trough concentration measurements could identify JIA patients who require increased adalimumab doses to achieve or maintain therapeutic drug concentrations.

Therapeutic Drug Monitoring in Patients with Suboptimal Response to Adalimumab for Hidradenitis Suppurativa: A Retrospective Case Series.

Adalimumab, a tumor necrosis factor-α inhibitor, is a biologic used for the treatment of moderate-to-severe hidradenitis suppurativa (HS). It is wellknown that patients may experience loss of efficacy from its use in other conditions, and it is suggested that developing a strategy for therapeutic drug monitoring (TDM) may help secure optimal clinical outcomes. We sought to determine serum adalimumab concentrations and anti-adalimumab antibody (AAA) status in patients with moderate-to-severe HS. A retrospective case series of 38 patients with suboptimal response to adalimumab 40mg weekly was conducted at a community dermatology clinic. Adalimumab serum trough levels, AAA status, and inflammatory biomarkers were collected. Blood was drawn on identification of suboptimal response (after a minimum of 12weeks) and was collected once prior to receiving the next scheduled dose. Kruskal-Wallis and Chi-squared tests were used for data analysis. A total of 38 patients had a median adalimumab trough concentration of 8.76 (interquartile range [IQR] 1.3-12.5) µg/mL. The median duration of adalimumab therapy of all patients was 21 (IQR 12-24) months. AAAs were detected in nine patients (24%), and all had subtherapeutic serum concentrations (< 6 µg/mL). Patients who were AAA+ had a significantly lower median adalimumab concentration than those who were AAA- (0.02µg/mL [range 0.02-0.81] vs. 10.14 [range 0.76-48.00]; p = 0.0006). Patients with AAAs had significantly lower serum adalimumab levels. The current study suggests that TDM may identify underlying reasons for suboptimal response and detect patients who may benefit from dose optimization strategies.

P479 The effect of adalimumab on linear growth in children with Crohn’s disease: a post hoc analysis of the PAILOT randomised control trial

Abstract Background Growth impairment is common in children with Crohn’s disease. We aimed to assess the effect of adalimumab treatment on linear growth in children with Crohn’s disease in a post-hoc analysis of the PAILOT randomised controlled trial. Methods Children 6–17 years old with moderate-to-severe Crohn’s disease, naïve to biologic treatment, who responded to adalimumab induction, were assessed at week 4, 8 andevery8 weeks thereafter until week 72 for anthropometric parameters (height, weight and body mass index, BMI, Z-scores). We also analysed the associations of these parameters with clinical disease activity, inflammatory biomarkers, faecal calprotectin and adalimumab trough concentration. Results Overall, 66 patients had available anthropometric parameters between week 4 to 72(29% females, mean age 14.3 ± 2.6 years). The median improvement of height z–score /month was +0.014, 95% CI 0.004–0.024, p = 0.006 with an overall improvement during the study period from -0.62 (IQR −1.6–0.15) to −0.33 (IQR -1.3–0.5). The median increase of weight z- score/month was +0.025, 95% CI 0.015–0.034, p = 0.025 [overall increase from -0.54 (IQR −1.2–0.15) to −0.1, (IQR -0.9–0.6)], whereas the median increase in BMI z –score/month was +0.02, 95% CI 0.008–0.031, p = 0.001 [overall increase from −0.4 (IQR −1.0–0.5) to 0.0 (IQR −0.8–0.9)]. There was a significant correlation between paediatric Crohn’s disease activity index and erythrocyte sedimentation rate at week 4 and height z-score changes (p = 0.043 and p = 0.048), respectively, and a marginal correlation with C-reactive protein (p = 0.06). There was a significant correlation between sustained clinical and biologic remission (weeks 4–72) and changes in height z-score during follow-up (p = 0.001). Faecal calprotectin, adalimumab trough concentrations and combination therapy with an immunomodulator were not associated with height z-score changes. Conclusion Adalimumab treatment significantly improved linear growth, and normalised weight and BMI in children with moderate-to-severe Crohn’s disease.

P718 Combination therapy of adalimumab with an immunomodulator is not more effective than adalimumab monotherapy in children with Crohn’s disease

Abstract Background The PAILOT trial was a randomised controlled trial aimed to evaluate proactive vs. reactive therapeutic drug monitoring in children with Crohn’s disease (CD) treated with adalimumab. Our aim, in this post-hoc analysis of the PAILOT trial, was to assess the efficacy and safety of adalimumab combination treatment in comparison to monotherapy at week 72 after adalimumab induction. Methods Participants were children 6–17 years old, biologic naïve, with moderate-to-severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline, maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit patients were assessed for disease index, serum biomarkers, faecal calprotectin, adalimumab trough concentration and anti-adalimumab antibodies. Results Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period there was no significant difference in the rates of sustained corticosteroid free clinical remission (25/34, 73% vs. 28/44, 63%; p = 0.35), and sustained composite outcome of clinical remission, CRP≤0.5 mg/dl and calprotectin≤150 µgr/gr (10/34, 29% vs. 14/44, 32%; p = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive sub-groups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but numerically higher in the monotherapy group. Conclusion Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD.

Combination Therapy of Adalimumab With an Immunomodulator Is Not More Effective Than Adalimumab Monotherapy in Children With Crohn's Disease: A Post Hoc Analysis of the PAILOT Randomized Controlled Trial.

The PAILOT trial was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn's disease (CD) treated with adalimumab. Our aim in this post hoc analysis of the PAILOT trial was to assess the efficacy and safety of adalimumab combination treatment in comparison with monotherapy at week 72 after adalimumab induction. Participants were children 6-17 years old, biologic naïve, with moderate to severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit, patients were assessed for disease index, serum biomarkers, fecal calprotectin, adalimumab trough concentration, and anti-adalimumab antibodies. Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period, there was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive subgroups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group. Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD (ClinicalTrials.gov No. NCT02256462).

746 Adalimumab Concentrations Following Dose Escalation in Inflammatory Bowel Disease

INTRODUCTION: Therapeutic drug monitoring is frequently performed for the management of inflammatory bowel disease (IBD). Adalimumab (ADA) concentrations of 12-16 ug/ml have been associated with clinical and endoscopic remission in Crohn's disease (CD) and ulcerative colitis (UC). The feasibility of achieving these concentrations following a dose escalation is unknown. We aim to determine expected rise in serum ADA concentrations in response to increased dose frequency. METHODS: Patients with an established diagnosis of IBD, on maintenance ADA therapy, and two ADA trough concentrations were included. The primary outcome was change in ADA concentration following dose escalation from every other week to weekly. Patients who had two concentrations without a dose escalation served as a control. Student's t-test was used to assess for significant differences in and between patients. Exploratory logistic regression was used to assess for clinical factors predicting the ability to achieve an ADA concentration &gt;12 ug/ml. RESULTS: Eighty-nine patients met inclusion criteria, 71% with CD, 23% with UC, and 6% with indeterminate colitis. Thirty six percent were on concurrent immunomodulator (IMM) therapy. Among patients on every other week ADA dosing, the initial mean ADA concentration for those who went on to a dose escalation was 3.7 ug/ml versus 9.7 ug/ml in those who did not dose escalate (P &lt; 0.001). Following dose escalation, mean ADA concentration significantly increased by 5.7 ug/mL (P &lt; 0.0001) compared to a significant decrease of 2.5 ug/mL (P &lt; 0.002) in those who remained on every other week dosing. This decrease was driven by IMM de-escalation (mean decrease of 1.7 ug/ml in those without IMM change, versus 5.5 ug/ml in those who stopped IMM, P &lt; 0.1). Exploratory logistic regression analysis identified initial ADA concentration, female sex, and ADA as first biologic as predictors of achieving an ADA concentration &gt;12 ug/ml after dose escalation. CONCLUSION: Among patients with an initial low ADA concentration, a dose escalation to weekly will increase the concentration by 5.7 ug/ml on average. Without dose escalation, cessation of IMM may decrease ADA concentrations by 5.5 ug/ml. Female sex, ADA as first biologic, and initial ADA concentration of ≥4.9 ug/ml all predicted the ability to achieve a concentration of &gt;12 ug/ml following dose escalation. The expected concentration change after ADA dose escalation can help to guide treating physicians in determining when dose escalation is appropriate.

Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn’s Disease Compared With Reactive Monitoring

Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n= 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n= 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P= .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoringgroup (12%) (P= .003). By week 72 of treatment, 33patientsin the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patientsin the reactivemonitoring group (60%) (P= .001). In a randomized controlled trial of pediatric patients with CD, we foundthat proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resultedin significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.

The effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in paediatric patients with Crohn's disease: a post hoc analysis.

In the IMAgINE 1 study, adalimumab induced and maintained remission of moderate-to-severe Crohn's disease in children. To assess the efficacy, pharmacokinetics, immunogenicity and safety of immunomodulator and adalimumab combination therapy vs adalimumab monotherapy in paediatric patients with Crohn's disease. Patients 6-17years old with moderate-to-severe Crohn's disease (n=192) received weight-based adalimumab induction at baseline and week 2. At week 4, 188 patients were randomised to high-dose or low-dose adalimumab. Patients receiving immunomodulators (investigator's decision) at baseline maintained a stable dose until week 26; patients could then discontinue immunomodulators. Adalimumab serum concentrations were measured at weeks 4, 26 and 52. Safety was evaluated at each study visit. Data were analysed using non-responder imputation (NRI; week 4) or modified NRI (weeks 26; 52). At week 4, patients with (n=117) and without (n=71) baseline immunomodulator use had similar response (79%; 87%; P=0.235) and remission (26%; 30%; P=0.737) rates. At week 26, patients with and without baseline immunomodulators had no significant difference in response (68%; 55%; P=0.086) or remission (41%; 30%; P=0.122). At week 52, patients with (n=82) and without (n=106) immunomodulator use had no significant difference in response (56%; 46%; P=0.189) or remission (38%; 33%; P=0.539). Adalimumab serum trough concentrations and serious infection rates (7%; 6%) were not significantly different between groups. Analyses found no statistically significant difference in response or remission between patients receiving adalimumab monotherapy vs immunomodulator and adalimumab combination therapy. Serious and infectious adverse event rates were similar between groups.

Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases.

Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints-such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially insituations of treatment failure.

Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial

ObjectiveHigh adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations >8 µg/mL can prolong their...

Editorial: variability in adalimumab trough and peak serum concentrations – authors’ reply

Linked ContentThis article is linked to Ward et al and Vande Casteele, Gils papers. To view these articles visit https://doi.org/10.1111/apt.13992 and https://doi.org/10.1111/apt.14049.

Four-year maintenance treatment with adalimumab in Japanese patients with moderately to severely active ulcerative colitis

BackgroundThe 52-week safety and efficacy of adalimumab in Japanese patients with moderately to severely active ulcerative colitis were demonstrated in a placebo-controlled phase 2/3 trial. Data from patients who enrolled in the open-label extension study are presented.MethodsRemission and response per the full Mayo score (FMS) and the partial Mayo score (PMS), remission per the Inflammatory Bowel Disease Questionnaire (IBDQ) score, corticosteroid-free remission, and mucosal healing were assessed up to week 196 (week 208 for remission/response per PMS) of adalimumab treatment in patients who received one or more doses of adalimumab with use of a hybrid nonresponder imputation (hNRI) method. Nonresponder imputation was used for missing data up to the latest possible follow-up date for each patient, followed by observed case. Adalimumab trough concentrations were reported from week 52 to week 196 of treatment. Treatment-emergent adverse events were reported for all adalimumab-treated patients.ResultsTwo hundred sixty-six patients received adalimumab. At week 196 of treatment, remission and response rates per FMS, remission and response rates per PMS, remission rate per IBDQ score, mucosal healing rate, and corticosteroid-free remission rate were 19.2%, 32.2%, 22.5%, 32.5%, 33.1%, 30.5% (hNRI), and 40.5% (17/42; as observed), respectively. Serum adalimumab concentrations remained constant in patients receiving 40 mg every other week but increased in patients who underwent dose escalation. The safety profile was consistent with that in the 52-week study.ConclusionsThe efficacy of adalimumab in Japanese patients with moderately to severely active ulcerative colitis was maintained for up to 4 years of treatment. No new safety signals were observed.

Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis: A Step Toward Personalized Treatment.

Adalimumab has proven to be effective in suppressing psoriasis disease activity and is administered in a standard dose. To establish a therapeutic range for adalimumab trough levels in the treatment of plaque-type psoriasis, leading to a more personalized treatment. A multicenter, prospective, observational, daily practice cohort study conducted at an academic hospital with affiliated secondary care hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2). Both cohorts included adult patients treated with adalimumab for plaque-type psoriasis. Cohort 1 comprised 73 patients who were being treated with adalimumab for more than 24 weeks until 401 weeks. In cohort 2 (n = 62), serum samples were obtained between weeks 24 and 52 of treatment. Before the start of adalimumab therapy and at time of serum sampling, Psoriasis Area and Severity Index (PASI) scores were determined. Adalimumab trough level and PASI score at the time of serum sampling to determine the receiver-operator characteristics analyses and concentration effect curve. By means of receiver-operator characteristics analyses with an area under the curve of 0.756 (SD, 0.046; 95% CI, 0.666-0.847) and a sensitivity of 78% and a specificity of 70%, 3.51 mg/L was established as the lower margin for the therapeutic range. By means of a concentration effect curve, 7 mg/L was established as the upper margin. One-third of patients had an adalimumab trough concentration exceeding 7 mg/L. A therapeutic range of adalimumab trough levels of 3.51 mg/L to 7.00 mg/L, which corresponds to an optimal clinical effect, was identified. In one-third of patients, it was observed that trough concentrations exceeded the therapeutic window. Based on the established range, a therapeutic algorithm for adalimumab treatment for patients with psoriasis can be developed and validated in a prospective patient cohort. By identifying this range, a step has been taken toward a more rational use of biological therapy in psoriasis. Developing a therapeutic algorithm may lead to less overtreatment of patients and cost savings.

OP0252 Adalimumab Serum Concentrations in Patients with Rheumatoid Arthritis or Psoriatic Arthritis Taking Concomitant DMARD Therapy

BackgroundAn important factor influencing pharmacokinetics of adalimumab is immunogenicity. There is a dose-dependent effect of methotrexate (MTX) on the amount of anti-drug antibodies produced against adalimumab [1]. Consequently, patients concomitantly...

OP0074 A Concentration-Effect Curve of Adalimumab in Patients with Psoriatic Arthritis

BackgroundIn rheumatoid arthritis the concentration-effect relationship of adalimumab has been investigated.[1] However, in psoriatic arthritis (PsA) there is a lack of knowledge about the pharmacodynamics and pharmacokinetics of adalimumab.ObjectivesTo investigate...

Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years

The objective of this study was to assess the safety of adalimumab in patients aged 2 to <4 years old or ≥4 years old weighing <15 kg with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). Clinical effectiveness and pharmacokinetics (PK) of adalimumab were also evaluated. This was an international, multicenter, open-label, phase 3b study in 32 patients with active JIA that were treated with adalimumab 24 mg/m2 (maximum = 20 mg/dose) every other week up to 120 weeks, with or without concomitant methotrexate. Adverse events (AEs) were summarized for completed visits. Efficacy endpoints included American College of Rheumatology pediatric (PedACR) 30/50/70/90 responses and JIA core components. Adalimumab serum trough concentrations were measured in a subset of patients. Among the patients, 88 % were female. Baseline mean age, weight, and JIA duration were 3 years, 13 kg, and 12 months, respectively; 39 % had elevated C-reactive protein. AE incidence rates included any AEs (29/32, 91 %), serious AEs (5/32, 16 %), infectious AEs (25/32, 78 %), and serious infections (3/32, 9 %). No deaths, malignancies, or opportunistic infections were reported. Growth was not adversely impacted. At week 96, 92 % of patients achieved PedACR30, and 77 % achieved PedACR70. Improvements in JIA core components were observed. Mean steady-state serum adalimumab trough concentrations were 7–8 μg/mL at weeks 12 and 24. Adalimumab was well tolerated in JIA patients aged 2 to <4 years old or ≥4 years old weighing <15 kg. The efficacy and PK of adalimumab were comparable to those seen in older JIA patients.