Population Pharmacokinetics of Adalimumab in Juvenile Idiopathic Arthritis Patients: A Retrospective Cohort Study Using Clinical Care Data.

BACKGROUND AND OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. MATERIALS AND METHODS: Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. RESULTS: A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. CONCLUSIONS: Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.

Signal-to-noise ratio to assess magnitude, kinetics and impact on pharmacokinetics of the immune response to an adalimumab biosimilar.

Background: The antidrug antibody (ADA) signal-to-noise (S/N) ratio was explored as a novel immunogenicity measure to evaluate the immune response of healthy subjects to a single dose of GP2017, an adalimumab biosimilar. Methodology/results: Bioanalytical methods used for the analysis of ADA S/N ratios and ADA titers were validated for sensitivity, precision and drug interference. ADA S/N ratios strongly correlated with ADA titers. Correlations between ADA area under the curve and ADAmax and pharmacokinetics (PK) were stronger for ADA S/N ratio than for ADA titers. Conclusion: ADA S/N ratio allowed for a more sensitive evaluation of the magnitude and kinetics of the immune response, was better correlated with adalimumab PK and was superior to ADA titers in assessing the impact of the immune response on PK.

High BMI is associated with lower TNF-α inhibitor serum trough levels and higher disease activity in patients with axial spondyloarthritis.

BACKGROUND: TNF-α inhibitor (TNFi) serum trough levels have previously been found to be related to disease activity in axial spondyloarthritis (axSpA). However, most research regarding serum trough levels has been conducted in patients who only recently started TNFi therapy. Therefore, our objective was to explore TNFi serum trough level measurements in relation to disease activity and BMI in the total axSpA population in daily clinical practice, also including patients on long-term TNFi therapy. METHODS: Consecutive patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were approached for a TNFi serum trough level measurement during their regular outpatient visit at the UMCG. Spearman's correlation coefficient was used to analyse the relation of serum trough levels with disease activity and BMI. Logistic regression was performed to analyse the relation between therapeutic drug levels and disease activity, corrected for potential confounders, including BMI. RESULTS: Thirty-four patients on adalimumab and 21 patients on etanercept were included. Mean age was 45 ± 12 years, 47% were male, median BMI was 26.4 (IQR 23.9-32.5) and median treatment duration was 41 months (range 2-126). According to definitions of Sanquin, 47% of patients had therapeutic serum trough levels. No significant correlations were found between TNFi levels and disease activity (ASDAS-CRP: adalimumab: ρ = -0.16, p = 0.39; etanercept: ρ = -0.29, p = 0.20). TNFi levels were moderately correlated with BMI (adalimumab: ρ = -0.48, p = 0.004; etanercept: ρ = -0.50, p = 0.021). Patients with active disease (ASDAS ≥ 2.1) showed higher BMI than patients with inactive disease (median 29.7 vs. 24.6, p = 0.015). In multivariable regression analyses, BMI was identified as the only confounder for the relationship between therapeutic drug levels and ASDAS. CONCLUSION: In this cross-sectional, observational study of axSpA patients mainly on long-term treatment with TNFi, higher BMI was significantly associated with lower adalimumab and etanercept serum trough levels and higher disease activity.

A randomized, double-blind, 3-arm, parallel study assessing the pharmacokinetics, safety, tolerability and immunogenicity of AVT04, an ustekinumab candidate biosimilar, in healthy adults.

BACKGROUND: This study assessed pharmacokinetic (PK) similarity, safety, and immunogenicity of AVT04, a candidate biosimilar, compared with reference product (RP) ustekinumab (EU-approved and US-licensed Stelara®). METHODS: Healthy subjects (N = 298) were randomized 1:1:1 to receive one 45 mg dose of AVT04, EU-RP, or US-RP. The primary PK parameters were Cmax and AUC0-inf. PK similarity was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means were all contained within the prespecified margins of 80% and 125%. Additional PK parameters, including AUC0-t, were also assessed. Safety and immunogenicity were also assessed until Day 92. RESULTS: After pre-specified protein content normalization, the 90% CI for the ratio of geometric means for primary PK parameters were all contained within the pre-specified bioequivalence margins of 80% and 125%, supporting demonstration of PK similarity between AVT04 and both EU- and US-RP. Secondary PK parameters supported the analysis. Safety and immunogenicity profiles were comparable across all three treatment arms, although the study was not powered to detect small differences in these parameters. CONCLUSION: Results supported a demonstration of PK similarity between candidate biosimilar AVT04, US-RP and EU-RP. Similar safety and immunogenicity were also shown.Clinical trial registration: www.clinicaltrials.gov identifier is NCT04744363.

Pharmacokinetics and safety of CT-P17 (40 mg/0.4 ml) versus reference adalimumab: randomized study in healthy Japanese adults.

Aim: Comparing pharmacokinetics and safety of CT-P17 and EU-approved reference adalimumab (EU-adalimumab) in Japan. Materials & methods: Double-blind, parallel-group phase I trial at three hospitals. Healthy Japanese adults were randomized (1:1) to CT-P17 or EU-adalimumab (single 40-mg subcutaneous dose). The primary end point was pharmacokinetic equivalence for area under the concentration-time curve from time zero to infinity and maximum serum concentration. Results: Of the 205 randomized subjects (102 CT-P17, 103 EU-adalimumab), 204 received study drug. CT-P17 and EU-adalimumab were pharmacokinetically equivalent: 90% CIs for geometric least-squares mean ratios were within predefined 80-125% equivalence margins. Secondary pharmacokinetic end points, safety and immunogenicity were similar between the groups. Conclusion: CT-P17 had pharmacokinetics, safety and immunogenicity comparable to EU-adalimumab in healthy Japanese adults.

CT-P17 is a biosimilar that has been determined by the EMA to be highly similar to adalimumab. CT-P17 is approved to treat the same inflammatory conditions as reference adalimumab. CT-P17 is formulated at a high concentration (40 mg/0.4 ml) and may be associated with less injection-site pain than the original lower-concentration formulation of the reference product. In this study, healthy Japanese adults were given a single dose of either CT-P17 or EU-approved reference adalimumab. Pharmacokinetics (drug absorption, distribution, metabolism and excretion), safety and immunogenicity (occurrence of immune response to the drug) were comparable between the two groups. Previous studies with CT-P17 did not take place in Japan. These results support applying the conclusions regarding CT-P17 biosimilarity from other studies to the Japanese population.

An Update Review of Biosimilars of Adalimumab in Psoriasis - Bioequivalence and Interchangeability.

Biologic drugs have revolutionized the treatment of psoriasis and other rheumatological diseases. In recent years, many biosimilar agents that are highly similar in structure and function to their originator products have been developed, including the tumor necrosis factor-alpha antagonist adalimumab. The considerably lower cost of these products has greatly cut the economic burden of the patients and increased the accessibility of biologic therapies worldwide. The US Food and Drug Administration and/or the European Medicines Agency have approved eight biosimilars of adalimumab (ABP 501/BI 695501/SB5/GP2017/FKB327/MSB11022/PF-06410293/CT-P17) for the treatment of psoriasis, and others are under review. Given that these agents showed pharmacokinetic, efficacy, safety, and immunogenicity profiles comparable to those of the originator, adalimumab biosimilars were licensed for all indications approved for reference adalimumab based on extrapolation; however, some of the equivalence studies were only conducted in one or two disease populations. This review discusses the bioequivalence of adalimumab biosimilars as demonstrated by various clinical trials, the extrapolation of indications, guidance and policies of the EU and US on interchangeability (nonmedical switching/automatic substitution) between biosimilars and originators, and the real-life practices of switching from reference adalimumab to the respective biosimilars. Further data from real-world studies and post-marketing analyses are needed better to address the efficacy and safety of the transition strategy.

Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease.

Adalimumab (ADA) trough level and anti-ADA antibody (AAA) positivity influence mucosal healing and loss of response in patients with inflammatory bowel disease (IBD). In this study, we clarified the correlation between ADA monitoring, including non-trough level, and real-world IBD clinical outcomes. This retrospective, observational, single-center study involved patients with ulcerative colitis (19) and Crohn's disease (33) treated with ADA from January 2007 to August 2018. Serum ADA and AAA levels were measured 4‒14 days after ADA administration. The AAA positivity rate was 23.1% (12/52). ADA continuity was higher in AAA-negative patients than in AAA-positive patients (P = 0.223). Receiver operating characteristic (ROC) analysis revealed that a serum AAA cut-off of 9.2 µg/mL was associated with ADA continuity. The ADA level was significantly higher in the endoscopic remission group than in the non-remission group (P = 0.02). Based on the ROC curve analysis results of serum ADA level and endoscopic remission, the cut-off value of the serum ADA level was set to 11.1 µg/mL. Under the combined use of ADA with immunomodulators and AAA positivity, ADA continuity was significantly higher when the serum AAA level at 4-14 days after ADA administration was ≥9.2 µg/mL. Furthermore, endoscopic remission can be expected with a serum ADA level of ≥11.1 µg/mL. Overall, to predict clinical outcomes, it would be useful to measure the blood level of ADA regardless of the timing of the trough.

A novel method for the storage and transport of biological samples of therapeutic proteins prior to the detection of analytes using ELISA.

Therapeutic proteins have exhibited promising clinical applications in the diagnosis and treatment of some diseases. Prior to the detection of analytes using enzyme-linked immunosorbent assay, biological samples of therapeutic proteins are conventionally frozen at temperatures ranging from - 20 to - 80 °C to increase the stability of analytes. However, therapeutic proteins destabilization and aggregation may occur during the frozen storage or the freeze-thawing step. In this work, an effective method was proposed to freeze-dry therapeutic protein samples to allow subsequent storage or transport of samples without freezing them. This new method was validated with quality control samples of adalimumab and etanercept, and it was also used in the bioanalysis of adalimumab and etanercept in pharmacokinetic (PK) studies. Adalimumab and etanercept were stable for 14 days at 4 °C after being prepared and stored using the new method, with detection that was accurate and repeatable. Studies of adalimumab and etanercept in animals and humans showed that the PK parameters of the analytes stored with the new method were consistent with those of analytes stored using the conventional method. This effective method will be attractive for facilitating the storage and transport of plasma samples containing therapeutic proteins.

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

OBJECTIVE: The objective of this study was to assess the relationship between adalimumab trough concentrations and treatment response in paediatric patients with JIA. METHODS: This was a 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 of ≤5mg/l. Disease activity was evaluated using the clinical Juvenile Arthritis DAS with 71-joint count (cJADAS71). Response to adalimumab was defined according to recent international treat-to-target guidelines. RESULTS: A total of 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; interquartile range (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. CONCLUSION: Adalimumab trough concentrations were significantly lower in JIA patients with secondary failure compared with patients with primary failure or an adequate response to adalimumab. Our results suggest that trough concentration measurements could identify JIA patients who require increased adalimumab doses to achieve or maintain therapeutic drug concentrations.

Pharmacokinetics, safety, and immunogenicity of HLX03, an adalimumab biosimilar, compared with reference biologic in healthy Chinese male volunteers: Results of a randomized, double-blind, parallel-controlled, phase 1 study.

The primary objective of this randomized, double-blind, parallel-controlled study (from December 2016 to October 2018) was to evaluate pharmacokinetic (PK) equivalence of adalimumab biosimilar HLX03 and reference adalimumab in healthy volunteers, and to assess safety, and immunogenicity of HLX03. The primary PK endpoints were maximum observed plasma concentration (Cmax ) and area under the concentration curve from time zero to the last quantifiable concentration (AUC0-t ). Equivalence was determined if the 90% confidence interval (CI) of geometric least square mean ratio between the two treatment groups were within the predefined range of 80%-125%. Safety and immunogenicity were monitored during the study. Healthy Chinese males (N = 220) were randomized 1:1 to receive a single subcutaneous 40 mg dose of HLX03 or China (CN)-sourced adalimumab. The ratios of the geometric mean of Cmax and AUC0-t were 102.2% and 105.7%, respectively, with corresponding 90% CIs falling in the predefined margins, which demonstrated PK equivalence between HLX03 and CN-adalimumab. The incidence of treatment-emergent adverse events (TEAEs) was similar in the two groups (73.8% and 66.0% in the HLX03 and CN-adalimumab groups, respectively). Grade 3-4 TEAEs were reported in 7.5% and 5.7% of participants, respectively. The incidences of participants with antidrug antibodies (HLX03: 96.2%; CN-adalimumab: 93.4%) or neutralizing antibodies (HLX03: 40.6%, CN-adalimumab: 41.4%) were comparable between groups. This study demonstrated PK bioequivalence between HLX03 and CN-adalimumab, with similar safety and immunogenicity profiles. These data support further clinical development of HLX03 as an adalimumab biosimilar.

Pharmacokinetic equivalence of CT-P17 to high-concentration (100 mg/ml) reference adalimumab: A randomized phase I study in healthy subjects.

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT-P17 to United States-licensed adalimumab (US-adalimumab) and European Union-approved adalimumab (EU-adalimumab). This double-blind, parallel-group, phase I trial (clinicaltrials.gov NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT-P17, US-adalimumab, or EU-adalimumab. Primary end points were PK equivalence in terms of: area under the concentration-time curve from time zero to infinity (AUC0-inf ); AUC from time zero to the last quantifiable concentration (AUC0-last ); and maximum serum concentration (Cmax ). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80-125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT-P17; 103 US-adalimumab; 106 EU-adalimumab), 308 subjects received study drug. AUC0-inf , AUC0-last , and Cmax were equivalent among CT-P17, US-adalimumab, and EU-adalimumab, because 90% CIs for the ratios of GLSMs were within the 80-125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single-dose administration of CT-P17, EU-adalimumab, and US-adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

Is There a Role for Therapeutic Drug Monitoring in Patients with Hidradenitis Suppurativa on Tumor Necrosis Factor-α Inhibitors?

Tumor necrosis factor-α inhibitors, adalimumab and infliximab, are at the forefront of biologic therapy for the management of moderate-to-severe hidradenitis suppurativa, with adalimumab as currently the only approved medication for this condition. In treating patients, primary or secondary lack of response (also termed suboptimal response) is a major burden for both patients and healthcare systems and is a challenge with biologics in part owing to the development of anti-drug antibodies following treatment. To overcome this, therapeutic drug monitoring may be conducted proactively or reactively to a patient's suboptimal response guided by measurements of trough serum drug concentrations and levels of anti-drug antibodies. While strong evidence to support the utility of therapeutic drug monitoring exists in patients with inflammatory bowel disease, current information is limited in the context of hidradenitis suppurativa. We sought to summarize the available evidence and to present the role of therapeutic drug monitoring and other dose optimization strategies in improving clinical response in patients with hidradenitis suppurativa treated with tumor necrosis factor-α inhibitors.

Adalimumab Concentration Changes After Dose Escalation in Inflammatory Bowel Disease.

BACKGROUND: Dose escalation of adalimumab (ADA) for loss or response in inflammatory bowel disease (IBD) is a common practice. Recent data suggest improved outcomes with an ADA concentration of 12 mcg/mL, but limited data are available on the ability to achieve a target concentration. The aim of this study was to determine the expected change in serum ADA concentration after a dose escalation performed every 7 days in patients with IBD. METHODS: A retrospective cohort of patients with IBD receiving ADA was divided into every fourteen-day dosing, every 7-day dosing, and dose escalation (ie, q14 to q7 day dosing). The primary outcome was the change in ADA concentration. Multiple logistic regression was performed to identify predictors of achieving a target ADA concentration of ≥12 mcg/mL. RESULTS: Overall, 380 patients were identified, of whom 200 underwent dose escalation, 100 remained on q14 days dosing, and 80 were maintained on q7 day dosing. After dose escalation, the mean ADA concentration increased by 5.5 mcg/mL (P < 0.0001). After dose escalation, a significant proportion of patients achieved an ADA concentration ≥12 mcg/mL (P = 0.0019), as well as clinical remission (P = 0.0053). Based on multiple logistic regression, age of <46 years [odds ratio (OR): 2.4; 95% confidence interval (CI): 1.3, 4.6; P < 0.01], body mass index of <29 (OR: 0.21; 95% CI: 0.1, 0.5; P < 0.0001), and initial ADA concentration of ≥3.0 mcg/mL were found to be associated with a target ADA concentration ≥12 mcg/mL (OR: 4.76; 95% CI: 2.3, 9.7; P < 0.0001). CONCLUSIONS: The average expected increase in serum ADA concentration after dose escalation from q14 to q7 days was 5.5 mcg/mL. The initial ADA concentration, age, and body mass index may influence the ability to achieve a target ADA concentration after dose escalation.

A Randomized, Double-Blind, Parallel-Group, Phase 1 Clinical Trial Comparing the Pharmacokinetic, Safety, and Immunogenicity of the Biosimilar HS016 and the Originator Adalimumab in Chinese Healthy Male Subjects.

A comparison of the immunogenicity, safety, and pharmacokinetic properties of HS016 and its originator, adalimumab, was conducted in Chinese healthy male subjects. This was a phase 1 single-center, randomized, parallel-group double-blind clinical trial. Chinese healthy male subjects (1:1) allocated to HS016 and adalimumab groups were treated with single subcutaneous injections (40 mg/0.8 mL). The pharmacokinetic equivalence of HS016 and adalimumab was assessed by (1) the area under the plasma concentration-time curve (AUC) from time 0 to the last detectable drug concentration (AUC0-t ), (2) the AUC from time 0 extrapolated to infinity (AUC0-∞ ), and (3) the maximum plasma concentration (Cmax ). Other pharmacokinetic parameters (time to Cmax , apparent clearance, and half-life), safety, and immunogenicity were also evaluated. A total of 136 subjects were randomly divided into HS016 (n = 68) or adalimumab (n = 68) groups. The geometric means of AUC0-t , AUC0-∞ , and Cmax were similar for HS016 and adalimumab. The 90%CIs of AUC0-t (87.2% to 106.1%), AUC0-∞ (87.4% to 108.4%), and Cmax (98.6% to 113.6%) were all within the prespecified bioequivalence criteria (80% to 125%). The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups, with most TEAEs being mild; only 3 (4.4%) subjects in the HS016 group experienced moderate TEAEs. No significant differences in the time to Cmax , apparent clearance, half-life, and immunogenicity were detected. The pharmacokinetic profile of HS016 was equivalent to that of the originator, adalimumab, with similar safety and immunogenicity profiles. HS016 may be considered for assessment in the treatment of patients with ankylosing spondylitis.

No Difference of Adalimumab Pharmacokinetics When Dosed at 40 mg Every Week or 80 mg Every Other Week in IBD Patients in Clinical Remission After Adalimumab Dose Intensification.

INTRODUCTION: The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems. AIM OF THE STUDY: To compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens. PATIENTS AND METHODS: This was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test. RESULTS: Sixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week. CONCLUSIONS: In IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient's preference for the latter regimen, a modification of injection regimen should be systematically proposed.

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

BACKGROUND: Adalimumab, a tumor necrosis factor-α inhibitor, is a biologic used for the treatment of moderate-to-severe hidradenitis suppurativa (HS). It is well known 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. OBJECTIVES: We sought to determine serum adalimumab concentrations and anti-adalimumab antibody (AAA) status in patients with moderate-to-severe HS. METHODS: A retrospective case series of 38 patients with suboptimal response to adalimumab 40 mg 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 12 weeks) and was collected once prior to receiving the next scheduled dose. Kruskal-Wallis and Chi-squared tests were used for data analysis. RESULTS: 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- (0.02 µg/mL [range 0.02-0.81] vs. 10.14 [range 0.76-48.00]; p = 0.0006). CONCLUSION: 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.

Hydrogel eye drops as a non-invasive drug carrier for topical enhanced Adalimumab permeation and highly efficient uveitis treatment.

Uveitis is one of the most popular blind-causing eye diseases worldwide. Adalimumab (ADA) is used for the uveitis treatment through systemic or intravitreal injection at the expense of systemic side effects and increased medical risks. Although eye drops, a non-invasive topical treatment, could be a potential strategy to reduce side effects, it remains challenging to apply due to limited bioavailability mainly linked to poor retention time and permeation capacity for eye biological barriers. Here, we reported hydrogel eye drops composed of low-deacetylated chitosan and ß-glycerophosphate as an ADA carrier and tested its toxicity, tolerability, intraocular permeability, and efficacy of non-invasive treatment for uveitis. It's found the ADA-loaded hydrogel eye drops were more efficient than free ADA both in permeation rate and clinical efficacy for uveitis, Overall, this study provides a friendly non-invasive strategy to improve drug permeation rate and uveitis treatment efficacy, which may be valuable to clinically ophthalmic medication.

Higher Maintenance Adalimumab Trough Levels are Associated With Achievement of Advanced Remission Targets in Patients With Inflammatory Bowel Disease.

BACKGROUND: Biomarker normalization and endoscopic remission are superior to clinical remission in achieving improved long-term clinical outcomes in patients with inflammatory bowel diseases. GOAL: To study whether higher maintenance adalimumab levels are associated with clinical remission, biomarker normalization, and endoscopic remission. STUDY: Data were collected retrospectively from the patients' medical records. We defined clinical remission as a Harvey Bradshaw Index ≤5 or a partial Mayo score ≤2 for Crohn's disease (CD) and ulcerative colitis (UC), respectively, biomarker normalization as a C-reactive protein <0.5 mg/dL and/or calprotectin <250 (mg/kg), endoscopic remission as a (simple endoscopic score-CD) ≤3/4 for ileal/extensive CD, respectively, or an endoscopic Mayo score ≤1 for UC, and deep remission as the combination of clinical and endoscopic remission with normal biomarkers. RESULTS: Ninety-seven patients were included (82 CD and 15 UC). Patients who achieved clinical remission, biomarker normalization, or endoscopic remission had higher serum trough adalimumab levels compared with patients not in remission [mean (M)±standard error (SE)=8.98±0.78 vs. 5.92±0.96 µg/mL; P=0.016, 9.38±0.85 vs. 5.48±0.87 µg/mL; P=0.002; 9.13±0.88 vs. 6.02±0.77 µg/mL; P=0.019, respectively]. Receiver-operating curve analysis showed that an adalimumab level of ≥8.25 µg/mL was associated with deep remission (sensitivity 84%, specificity 70%, area under the curve 0.775; P<0.001). CONCLUSION: Clinical remission, biomarker normalization, and endoscopic remission are positively associated with adalimumab trough levels. Adalimumab level of ≥8.25 µg/mL is associated with deep remission. This study provides additional data to guide therapeutic drug monitoring with adalimumab.

The Effect of Adiposity on Anti-Tumor Necrosis Factor-Alpha Levels and Loss of Response in Crohn's Disease Patients.

INTRODUCTION: A high body mass index is known to adversely affect antitumor necrosis factor-alpha trough levels and secondary loss of response (SLOR) in patients with Crohn's disease. We hypothesize that high levels of adiposity negatively affect these outcomes and aimed to determine if this relationship exists. METHODS: We performed a retrospective cross-sectional study of 69 patients with Crohn's disease from two tertiary inflammatory bowel disease centers between February 1, 2015, and June 30, 2018. Primary responders to infliximab (IFX) or adalimumab (ADA) who had a trough level performed within 6 months of CT or MRI scan and at least 12 months of clinical follow-up were eligible for inclusion. Body composition as measured on CT/MRI scans were correlated with trough concentration and time SLOR. Multivariate adjustments were made for established risk factors known to affect trough levels and SLOR. RESULTS: Of 69 included patients, 44 (63.8%) and 25 (36.2%) patients received IFX and ADA, respectively. Multivariate analysis revealed that IFX trough concentrations were inversely correlated with visceral fat area (-0.02 [-0.04, -0.003], P = 0.03), visceral fat index (-0.07 [-0.12, -0.01], P = 0.02) and visceral fat: skeletal muscle area ratio (-3.81 [-7.13, -0.50], P = 0.03), but not body mass index (-0.23 [-0.52, 0.06], P = 0.11). No predictive factors were found for ADA. Increased total adipose area was associated with an increased risk of SLOR in ADA-treated patients, but not IFX-treated patients (hazard ratio = 1.01 [1.002, 1.016], P = 0.011). DISCUSSION: Visceral adiposity is an important predictor of IFX trough levels, and high total adiposity predicts for SLOR to ADA.