Adalimumab Concentrations Research Articles

Infliximab and adalimumab concentrations and anti-drug antibodies in inflammatory bowel disease control using New Zealand assays.

Therapeutic drug monitoring of anti-tumour necrosis factor (TNF) drugs and anti-drug antibodies (ADA) is now recommended in the treatment of inflammatory bowel disease. However, assay types and drug concentration thresholds are still debated. To correlate inflammatory bowel disease activity in a New Zealand cohort with trough concentrations of infliximab and adalimumab, and ADA using locally developed competitive-binding enzyme-linked immunosorbent assays (ELISA) to establish threshold concentrations. Patients with ulcerative colitis (UC) and Crohn disease (CD) from Christchurch and Dunedin on anti-TNF drugs >12 weeks were enrolled. Trough blood samples were assayed for drug and ADA concentrations. Other data included quality of life, blood count, C-reactive protein, albumin, renal function and disease activity indices. Of 103 patients, 53 were on infliximab (36 CD, 15 UC and 2 unclassified) and 50 adalimumab (48 CD and 2 UC). Median (range) infliximab and adalimumab concentrations were 10.5 (0-41) and 9.61 mg/L (0-30). CD remission, Crohn Disease Activity Index <150, correlated with infliximab and adalimumab concentration in CD (infliximab, P = 0.03; adalimumab, P = 0.04), with too few UC patients for analysis. Receiver operator curve analysis suggested a threshold value of 5.1 mg/L for distinguishing active disease from remission for infliximab and 7.3 mg/L for adalimumab in CD. Of 13 patients with infliximab <2 mg/L, 10 were ADA positive by homogeneous mobility shift assay (HMSA), including five with neutralising antibodies using ELISA. Of six with adalimumab <2 mg/L, three were ADA positive using HMSA, including one with neutralising antibodies. Using the New Zealand ELISA assay, threshold concentrations of 5 mg/L for infliximab and 7 mg/L for adalimumab are suggested to aid dosing decisions, consistent with results internationally. Both neutralising (ELISA) and non-neutralising ADA (HMSA) are associated with low drug concentrations.

A multiplex liquid chromatography tandem mass spectrometry method for the quantification of seven therapeutic monoclonal antibodies: Application for adalimumab therapeutic drug monitoring in patients with Crohn's disease

The use of therapeutic monoclonal antibodies (mAbs) is steadily increasing. Previous studies have reported the clinical interest of mAb therapeutic-drug monitoring (TDM), including that of adalimumab, for patients with Crohn's disease (CD). Proof of concept mAb-quantification studies by liquid chromatography mass spectrometry (LC-MS/MS) have been published, but a specific and reliable routine-suited multiplex quantification method is still needed to facilitate mAb TDM.We describe an electrospray ionization LC-MS/MS method for the simultaneous quantification of seven mAbs (adalimumab, cetuximab, infliximab, rituximab, secukinumab, tocilizumab, and trastuzumab) in human plasma. Sample preparation was performed using protein-G purification and trypsin digestion to obtain proteotypic peptides. We retrospectively measured the adalimumab concentration in 65 plasma samples from 56 CD patients and determined the adalimumab therapeutic cut-off concentration associated with biological remission.Calibration curves were linear from 1 to 100 μg mL−1, except for rituximab (5–100 μg mL−1). This method was reproducible, repeatable, and accurate (coefficient of variation and bias < 20%), with no cross contamination. Adalimumab concentrations were significantly higher (p = 0.0198) for patients with biological remission (median: 11.3 μg mL−1 [4.6; 18.3]) than that for patients without a biological response (9.5 μg mL−1 [3.94;17.0]). An adalimumab cut-off concentration of 8.0 μg mL−1 correctly discriminated patients with or without biological remission (sensitivity: 74.1%, specificity: 57.9%).This validated LC-MS/MS routine-suited method is the first allowing simultaneous quantification of up to seven mAbs acting against different pharmacological targets. It opens the field of TDM to numerous mAbs.

M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model

The transfer of pathogenic immunoglobulin G antibodies from mother to fetus is a critical step in the pathophysiology of alloimmune and autoimmune diseases of the fetus and neonate. Immunoglobulin G transfer across the human placenta to the fetus is mediated by the neonatal Fc receptor, and blockade of the neonatal Fc receptor may provide a therapeutic strategy to prevent or minimize pathological events associated with immune-mediated diseases of pregnancy. M281 is a fully human, aglycosylated monoclonal immunoglobulin G1 antineonatal Fc receptor antibody that has been shown to block the neonatal Fc receptor with high affinity in nonclinical studies and in a phase 1 study in healthy volunteers. The objective of the study was to determine the transplacental transfer of M281 and its potential to inhibit transfer of immunoglobulin G from maternal to fetal circulation. To determine the concentration of M281 required for rapid cellular uptake and complete saturation of the neonatal Fc receptor in placental trophoblasts, primary human villous trophoblasts were incubated with various concentrations of M281 in a receptor occupancy assay. The placental transfer of M281, immunoglobulin G, and immunoglobulin G in the presence of M281 was studied using the dually perfused human placental lobule model. Immunoglobulin G transfer was established using a representative immunoglobulin G molecule, adalimumab, a human immunoglobulin G1 monoclonal antibody, at a concentration of 270 μg/mL. Inhibition of immunoglobulin G transfer by M281 was determined by cotransfusing 270 μg/mL of adalimumab with 10 μg/mL or 300 μg/mL of M281. Concentrations of adalimumab and M281 in sample aliquots from maternal and fetal circuits were analyzed using a sandwich enzyme-linked immunosorbent assay and Meso Scale Discovery assay, respectively. In primary human villous trophoblasts, the saturation of the neonatal Fc receptor by M281 was observed within 30-60 minutes at 0.15-5.0 μg/mL, suggesting rapid blockade of neonatal Fc receptor in placental cells. The transfer rate of adalimumab (0.23% ± 0.21%) across dually perfused human placental lobule was significantly decreased by 10 μg/mL and 300 μg/mL of M281 to 0.07 ± 0.01% and 0.06 ± 0.01%, respectively. Furthermore, the transfer rate of M281 was 0.002% ± 0.02%, approximately 100-fold lower than that of adalimumab. The significant inhibition of immunoglobulin G transfer across the human placental lobule by M281 and the minimal transfer of M281 supports the development of M281 as a novel agent for the treatment of fetal and neonatal diseases caused by transplacental transfer of alloimmune and autoimmune pathogenic immunoglobulin G antibodies.

Subcutaneous Absorption Contributes to Observed Interindividual Variability in Adalimumab Serum Concentrations in Crohn's Disease: A Prospective Multicentre Study.

Therapeutic drug monitoring is used to optimise adalimumab therapy in patients with Crohn's disease [CD]. However, the interindividual variability in drug absorption and the quantitative effect on drug clearance of anti-adalimumab antibodies [AAA], measured with a drug-resistant assay, are unclear. We aimed to characterise adalimumab population pharmacokinetics [PopPK] and identify determinants of interindividual variability in patients with CD. In a prospective multicentre open-label cohort study in 28 patients with CD starting adalimumab therapy peak, intermediate, and trough serum samples were analysed for adalimumab and AAA concentrations using a drug resistant assay. Adalimumab concentration-time data were analysed by non-linear mixed effects modelling and were adequately described by a PopPK model with first-order absorption and one-compartment disposition with linear elimination. Clinical remission at Week 12 [W12] was defined as a Harvey-Bradshaw index ≤4. The absorption rate, volume of distribution, and clearance estimates of a typical patient were respectively 0.343 /day, 7.8 L, and 0.330 L/day. A 4-fold difference in the range of adalimumab concentrations was observed 7 days after the first dose and found to be inversely correlated with baseline lean body weight [LBW], soluble tumour necrosis factor [s-TNF], and s-TNF receptor-1 whereas positive AAA and higher LBW were found to be important predictors of accelerated clearance. An adalimumab concentration at W12 of >7.3 µg/mL was significantly associated with achieving clinical remission at W12. Variability in subcutaneous drug absorption is an important contributor to the observed interindividual variability in adalimumab concentrations, in addition to drug clearance [ClinicalTrials.gov NCT02450513].

P660 Stability of serum concentrations of infliximab and adalimumab across pregnancy in IBD

P660 Stability of serum concentrations of infliximab and adalimumab across pregnancy in IBD

P431 Validation of a therapeutic drug monitoring test to measure the adalimumab biosimilar SB5 in comparison with the reference adalimumab

Validation of therapeutic drug monitoring (TDM) tests is an essential requirement for using these tools to help assess reasons for non-response. The arrival of biosimilars has prompted a need to validate that existing TDM tests are suitable to determine drug levels for all versions of a given molecule. The adalimumab (ADL) biosimilar SB5 (IMRALDI®, Biogen) was authorised by the European Commission in August 2017, and has recently become available for prescription in several European countries. Promonitor®-ADL test is routinely used to monitor IBD patients treated with ADL. In this study, we validated the suitability and performance of Promonitor-ADL CE-marked TDM test for quantifying SB5 serum concentrations in comparison to reference adalimumab (HUMIRA®, Abbvie). The study evaluated imprecision and bias applied to the reference ADL and SB5 biosimilar. The validation study was in line with the design requirements established in the Clinical and Laboratory Standards Institute (CLSI) guideline EP10-A3 for the determination of imprecision and bias. Imprecision was evaluated using three replicates of five human serum sample matrices representative of clinically relevant ADL concentrations and spanning the measurement range of Promonitor-ADL.1 Validations were ran on one instrument with one kit lot by one operator over six non-consecutive operating days and one run per testing day, with an acceptance criterium of CV% ≤20%. The Lower Limit of Quantification (LLOQ) of Promonitor-ADL was determined according to CLSI guideline EP17-A2. The imprecision of Promonitor-ADL was calculated by estimating the components of variance due to within-run and between-day factors meet the accuracy goals proposed at all concentration levels of SB5 vs. HUMIRA (CV% between 5% and 12%). The assessment of accuracy showed that Promonitor-ADL equally measures the active moiety of HUMIRA or SB5. The test is able to quantify SB5 in the measurement range of 0.9 to 10.9 μg/ml with a bias estimate of −0.124 (1%) to 0.897 (10%) μg/ml and an overall imprecision of 5% to 11%. The measurement range includes the recommended clinical decision points. LLOQ of the test to determine ADL was determined to be 0.36 μg/ml. This study demonstrates that Promonitor-ADL test can measure either the reference ADL drug or the biosimilar SB5 (IMRALDI) with equivalent sensitivity, precision and accuracy. Reference 1. Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology 2017;153:827–34.

Proactive Therapeutic Drug Monitoring of Adalimumab Is Associated With Better Long-term Outcomes Compared With Standard of Care in Patients With Inflammatory Bowel Disease.

Therapeutic drug monitoring [TDM] has proven to be effective for optimising anti-tumour necrosis factor [TNF] therapy in inflammatory bowel disease [IBD]. Nevertheless, the majority of data refer to infliximab and reactive testing or association studies. We aimed to compare the long-term outcome of patients with IBD who received at least one proactive TDM of adalimumab, with standard of care, defined as empirical dose escalation and/or reactive TDM. This was a multicentre retrospective cohort study. Patients on maintenance adalimumab therapy from June 2006 to December 2015 were eligible. We analysed time to treatment failure from start of adalimumab until the end of follow-up [July 2016]. Treatment failure was defined as drug discontinuation for secondary loss of response or serious adverse event or need for IBD-related surgery. Serum adalimumab concentrations and antibodies to adalimumab were measured using the Prometheus homogeneous mobility shift assay. A total of 382 patients with IBD [Crohn's disease, n = 311, 81%] were included and received either at least one proactive TDM [n = 53] or standard of care [empirical dose escalation, n = 279; reactive TDM, n = 50]. Patients were followed for a median of 3.1 years [interquartile range, 1.4-4.8 years]. Multiple Cox regression analyses showed that at least one proactive TDM was independently associated with a reduced risk for treatment failure (hazard ratio [HR]: 0.4; 95% confidence interval [CI]: 0.2-0.9; p = 0.022). This multicentre, retrospective cohort study reflecting real-life clinical practice provides the first evidence that proactive TDM of adalimumab may be associated with a lower risk of treatment failure compared with standard of care in patients with IBD.

Validation of a population pharmacokinetic model of adalimumab in a cohort of patients with inflammatory bowel disease.

therapeutic monitoring of anti-TNF drugs and anti-drug antibody levels are useful for clinical decision-making, via the rationalization and optimization of the use of anti-TNF treatments. The objective of the present study was to validate the model of Ternant et al., in a cohort of patients with inflammatory bowel diseases (IBD). This model was originally established for patients with rheumatoid arthritis and was used in this study to optimize the adalimumab (ADA) dose and predict ADA trough levels (ATL). this study used concentration data points from 30 IBD patients who received ADA treatment between 2014 and 2015. A goodness-of-fit of the model was determined by evaluating the relationship between the observed ATL values and population model-predicted values (PRED) or individual model-predicted values (IPRED). a total of 51 ADA concentration points were analyzed. The bias of the model was 2.39 (95% CI, 1.63-3.15) for PRED and 0.63 (95% CI, 0.23-1.03) for IPRED. The precision was 3.57 (95% CI, 2.90-4.13) and 1.53 (95% CI, 1.22-1.80), respectively. therapeutic drug monitoring involving ATL may allow the optimization of the treatment of IBD patients. The validation results of the phamacokinectic (PK) model for ADA in IBD patients are inadequate. However, additional studies will strengthen the bias and precision of the model.

32: M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex-vivo placental perfusion model

M281 is an anti-FcRn antibody which demonstrated IgG lowering in a phase I study in normal human subjects. The neonatal Fc receptor (FcRn) is required for transplacental IgG transfer and helps maintain serum IgG half-life. Inhibition of FcRn in severe alloimmune or autoimmune diseases of the fetus and neonate should inhibit pathogenic IgG transfer and improve fetal/neonatal outcomes. This ex vivo study evaluated M281’s ability to inhibit transplacental IgG transfer and tested M281’s potential for maternal to fetal transfer across the human placenta. Using the technique of dual perfusion of term human placental lobule, normal placentas were transfused with varying concentrations of M281 (0, 0.01, 0.3, 3 mg/ml) or adalimumab (270 μg/ml), a representative IgG, in the maternal reservoir to determine M281 blockade of maternal to fetal (M→F) transfer up to 6 hrs. To further investigate the M281 M→F transfer, studies were conducted with addition of M281 alone (0.3-20 mg/mL) in the maternal reservoir. Samples from maternal and fetal circuits were collected at time intervals to determine the concentrations of adalimumab and M281 in the perfusion medium using a sandwich ELISA and MSD method, respectively. Antipyrine (AP 100 μg/ml) was added as a marker compound to account for inter-placental variations. The M→F transfer rates (TRf, %) were calculated from the ratio of the concentration of the test substance in the fetal perfusate at the end of the experiment/concentration of the test substance in the maternal perfusate at the start of the experiment. The (M→F) transfer rate of AP was >40% in all experiments, indicating high perfusion overlap between the maternal and fetal circuits. Under these experimental conditions, the average TRf of M281 was 0.002 ± 0.002% (n=14), suggesting insignificant transfer of M281 across the placenta. The average TRf of adalimumab was 0.23 ± 0.21% (range 0.03 – 0.65%, n=8), which was decreased significantly in the presence of M281 to 0.06 ± 0.01%, p<0.01 (range 0.05 to 0.08%, n=5). This decrease was further observed to be independent of M281 concentration. Transfer of M281 across human placenta to the fetal circuit is minimal. M281 significantly decreased the transfer of adalimumab from maternal to fetal circuit. These findings support evaluation of M281 as a potential therapeutic agent for fetal and neonatal diseases caused by transplacental transfer of allo/auto-immune pathogenic IgG antibodies.

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.

Correlation Between Anti-TNF Serum Levels and Endoscopic Inflammation in Inflammatory Bowel Disease Patients

(a) To evaluate the diagnostic accuracy of anti-TNF trough levels to predict mucosal healing in inflammatory bowel disease (IBD); (b) to determine the best cut-off point to predict mucosal healing in IBD patients treated with anti-TNF. This is a multicenter, prospective study. IBD patients under anti-TNF treatment for at least 6months that had to undergo an endoscopy were included. Mucosal healing was defined as: Simple endoscopic score for Crohn's Disease < 3 for Crohn's disease (CD), Rutgeerts score < i2 for CD in postoperative setting, or Mayo endoscopic score ≤ 1 for ulcerative colitis (UC). Anti-TNF concentrations were measured using SMART ELISAs at trough. A total of 182 patients were included. Anti-TNF trough levels were significantly higher among patients that had mucosal healing than among those who did not. The area under the curve of infliximab for mucosal healing was 0.63 (best cutoff value 3.4μg/mL), and for adalimumab 0.60 (best cutoff value 7.2μg/mL). In the multivariate analysis, having anti-TNF drug levels above the cutoff values [odds ratio (OR) 3.1]) and having UC instead of CD (OR 4) were associated with a higher probability of having mucosal healing. Additionally, the need for an escalated dosage (OR 0.2) and current smoking habit (OR 0.2) were also associated with a lower probability of mucosal healing. There was an association between anti-TNF trough levels and mucosal healing in IBD patients; however, the accuracy of the determination of infliximab and adalimumab concentrations able to predict mucosal healing was suboptimal.

Exposure–response analyses demonstrate no evidence of interleukin 17A contribution to efficacy of ABT-122 in rheumatoid or psoriatic arthritis

ABT-122 is a dual-variable-domain immunoglobulin that neutralizes both TNF-α and IL-17A. The objective of this work was to characterize exposure-response relationships for ABT-122 relative to adalimumab (TNF-α inhibitor) using ABT-122 phase 2 trials in patients with RA or PsA. Patients received subcutaneous doses of ABT-122 ranging from 60 mg every other week (EOW) to 240 mg every week, adalimumab 40 mg EOW, or placebo (PsA patients only) for 12 weeks. Relationships between ABT-122 or adalimumab serum concentrations and time course of ACR20, ACR50 and ACR70 and PASI50, PASI75 and PASI90 responses were characterized using a non-linear mixed-effects Markov modelling approach. A total of 221 RA patients and 240 PsA patients were included in the analyses. At comparable molar exposures, there was no differentiation of efficacy between ABT-122 and adalimumab and there were no consistent differences between ABT-122 and adalimumab in the potency estimates for different efficacy endpoints based on the Markov models. Plateau of ABT-122 efficacy was achieved at exposures associated with the 120 mg EOW dose in patients with RA, which were comparable to molar exposures of adalimumab 40 mg EOW, and at the lowest dose of 120 mg every week in patients with PsA. The exposure-response relationships for ABT-122 were not distinguishably different from those of adalimumab in patients with RA or PsA. Overall, there was no clear evidence that inhibition of the IL-17 pathway provided incremental benefit in the presence of TNF-α inhibition. ClinicalTrials.gov, NCT02433340, NCT02349451.

Maintenance Adalimumab Concentrations Are Associated with Biochemical, Endoscopic, and Histologic Remission in Inflammatory Bowel Disease.

A treat-to-target therapeutic approach is emerging as the new standard of care for treating inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). We aimed to investigate the association of serum adalimumab concentrations during maintenance therapy with biochemical, endoscopic, and histologic remission in IBD. This retrospective multicenter study included consecutive IBD patients on adalimumab maintenance therapy who had a C-reactive protein (CRP) within 1week and/or endoscopic evaluation within 12weeks of therapeutic drug monitoring between July 2013 and December 2016. Biochemical remission was defined as a normal CRP (≤ 5mg/L). Endoscopic remission was defined as the absence of any ulceration/erosion or a Rutgeerts score of ≤ i1 for patients with an ileocolonic resection for CD and a Mayo endoscopic score of ≤ 1 for UC. Histologic remission was defined as the absence of any sign of active inflammation. Adalimumab concentrations were measured using the homogeneous mobility shift assay. Ninety-one CRP levels and 72 colonoscopies from 98 IBD patients [CD: n = 72 (73%)] were evaluated. Based on receiver operating characteristic analyses, we identified an adalimumab concentration threshold of 11.8, 12, and 12.2μg/mL in CD and 10.5, 16.2, and 16.2μg/mL in UC to stratify patients with or without biochemical, endoscopic, or histologic remission, respectively. Adalimumab concentrations ≥ 12μg/mL (OR 8; 95% CI 2-31.9; p = 0.003) and ≥ 12.2μg/mL (OR 9.6; 95% CI 1.7-56.1; p = 0.012) were independently associated with endoscopic and histologic remission in CD, respectively. This study demonstrates that higher maintenance adalimumab concentrations are associated with objective therapeutic outcomes in IBD.

Exposure Concentrations of Infants Breastfed by Women Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and Development

Exposure to biologic and immunosuppressant agents during breastfeeding is controversial, and there are limited data on safety. We investigated whether biologics are detectable in breast milk from women receiving treatment for inflammatory bowel diseases (IBDs) and whether breastfeeding while receiving treatment is associated with infections or developmental delays. We performed a multicenter prospective study of women with IBD and their infants, collecting breast milk samples (n= 72) from patients receiving biologic therapy from October 2013 to November 2015. Drug concentrations were measured in all breast milk samples at several time points within 48 hours of collection and within 168 hours for some samples. Child development was assessed using the Ages and Stages Questionnaire 3, completed by 824 women with IBD (treated or untreated) during pregnancy (620 breastfed, and 204 did not). Data on children's health and development were obtained from mothers and pediatricians, along with information on mothers' medication exposure, IBD history, activity, pregnancy, and postpartum complications. We used chi-squared method or Fisher exact test to determine associations between categorical values and compared differences in continuous outcomes between groups using analysis of variance models. The primary outcome was drug concentration of biologic agents in breast milk (from 72 women) at 1, 12, 24, and 48 hours after dosing and also at 72, 96, 120, and 168 hours for available samples. Secondary outcomes were a range of infant infections and Ages and Stages Questionnaire 3-defined developmental delays among all breastfed infants. We detected infliximab in breast milk samples from 19 of 29 treated women (maximum, 0.74μg/mL), adalimumab in 2 of 21 treated women (maximum, 0.71 μg/mL), certolizumab in 3 of 13 treated women (maximum, 0.29 μg/mL), natalizumab in 1 of 2 treated women (maximum,0.46 μg/mL), and ustekinumab in 4 of 6 treated women (maximum, 1.57 μg/mL); we did not detect golimumab in breast milk from the 1 woman receiving this drug. Rates of infection and developmental milestones at 12 months were similar in breastfed vs non-breastfed infants: any infection, 39%vs 39% in control individuals (P > .99) and milestone score, 87 vs 86 in control individuals (P= .9992). Rates of infection and developmental milestones did not differ among infants whose mothers received treatment with biologics, immunomodulators, or combination therapy compared with unexposed infants (whose mothers received treatment with mesalamines or steroids or no medication). In a study of women receiving treatment for IBD and their infants, we detected low concentrations of infliximab, adalimumab, certolizumab, natalizumab, and ustekinumab in breast milk samples. We found breastfed infants of mothers on biologics, immunomodulators, or combination therapies to have similar risks of infection and rates of milestone achievement compared with non-breastfed infants or infants unexposed to these drugs. Maternal use of biologic therapy appears compatible with breastfeeding. Clinicaltrials.gov no.: NCT00904878.

Development and validation of a targeted affinity-enrichment and LC–MS/MS proteomics approach for the therapeutic monitoring of adalimumab

BackgroundThe anti-tumor necrosis factor alpha (TNFα) therapeutic monoclonal antibodies (mAbs), such as adalimumab, are widely used in the treatment of rheumatoid arthritis, inflammatory bowel diseases, and other auto-immune diseases. The administration of adalimumab can elicit the immune responses from some patients, resulting in the formation of anti-drug antibodies (ADAbs). The ADAbs can diminish the therapeutic effects of adalimumab by neutralizing the TNFα binding site or increasing its clearance from circulation. MethodsTo effectively monitor the therapeutic concentrations of adalimumab, we developed and validated a targeted quantitative proteomic assay to determine the circulating concentrations of adalimumab. Since drug effects can be attenuated by ADAbs, the method adopted an affinity-enrichment step to selectively quantify the bioavailable forms of adalimumab in patient serum samples. ResultsThe performance of the LC–MS/MS based assay provides the analytical measuring range and precisions applicable for the therapeutic monitoring of adalimumab. It also provides comparable results to a cell-based activity assay when evaluating patient samples with different concentrations of adalimumab. ConclusionOur assay can quantify both sub-therapeutic and therapeutic concentrations of bioavailable adalimumab in patient serum samples. This assay design provides an alternative to isotope-labeled peptides approach currently adopted in targeted proteomics methods.

Methotrexate Dose in Patients With Early Rheumatoid Arthritis Impacts Methotrexate Polyglutamate Pharmacokinetics, Adalimumab Pharmacokinetics, and Efficacy: Pharmacokinetic and Exposure-response Analysis of the CONCERTO Trial

PurposeMethotrexate (MTX) and adalimumab are well-recognized treatments of rheumatoid arthritis (RA), the efficacy of which may be driven by intracellular polyglutamates (PGs). The aim of this analysis was to characterize MTX PG concentrations and adalimumab pharmacokinetics in the CONCERTO trial. In addition, the relationships between MTX dose/pharmacokinetics, adalimumab pharmacokinetics, and efficacy were evaluated. MethodsCONCERTO was a double-blind, parallel-arm study in patients with early RA randomized to adalimumab 40 mg SC every other week plus blinded MTX 2.5, 5, 10, or 20 mg PO once weekly, for 26 weeks. Blood samples were obtained through week 26 for the determination of concentrations of MTX PG, adalimumab, and anti-adalimumab antibody (AAA). Clinical outcomes were also assessed. FindingsA total of 395 patients were included in the analysis (MTX, 329; adalimumab, 395). The mean time to steady-state MTX PG concentration was increased with MTX dose, from 8 to >26 weeks, depending on PG chain length. Dose proportionality changed with PG chain length. As MTX dose was increased, the percentage of short-chain PGs increased less than dose proportionally, while the percentage of long-chain PGs increased more than dose proportionally. For very-long-chain PGs, dose proportionality could not be assessed due to the nonmeasurable concentrations in the 2.5- and 5-mg MTX dose groups. As MTX dose increased, mean adalimumab concentrations also increased (P < 0.001). The percentage of patients with AAA decreased with increasing MTX dose, and at week 26, AAA+ status was significantly correlated with MTX dose level (P = 0.005). In general, rates of response, defined using the 28-joint count disease activity score based on C-reactive protein (DAS28[CRP]; response, <3.2), were greater in the subgroup without AAA. The likelihood of a patient achieving a DAS28(CRP) response was related to the baseline measurement (P < 0.001) and to the concentration of adalimumab (P = 0.001), but not to the MTX regimen (P = 0.689). ImplicationsThe dose–response characteristics of MTX PG pharmacokinetics and the resultant effects of MTX on adalimumab exposures should be considered when determining the benefit–risk profile of MTX and adalimumab combination therapy in patients with early RA. ClinicalTrials.gov identifier: NCT01185301.

Anti-TNF Therapeutic Drug Monitoring in Postoperative Crohn's Disease.

Anti-TNF prevents postoperative Crohn's disease recurrence in most patients but not all. This study aimed to define the relationship between adalimumab pharmacokinetics, maintenance of remission and recurrence. As part of a study of postoperative Crohn's disease management, some patients undergoing resection received prophylactic postoperative adalimumab. In these patients, serum and fecal adalimumab concentration and serum anti-adalimumab antibodies [AAAs] were measured at 6, 12 and 18 months postoperatively. Levels of Crohn's disease activity index [CDAI], C-reactive protein [CRP] and fecal calprotectin [FC] were assessed at 6 and 18 months postoperatively. Body mass index and smoking status were recorded. A colonoscopy was performed at 6 and/or 18 months. Fifty-two patients [32 on monotherapy and 20 on combination therapy with thiopurine] were studied. Adalimumab concentration did not differ significantly between patients in endoscopic remission vs recurrence [Rutgeerts ≥ i2] [9.98µg/mL vs 8.43 µg/mL, p = 0.387]. Patients on adalimumab monotherapy had a significantly lower adalimumab concentration [7.89 µg/mL] than patients on combination therapy [11.725 µg/mL] [p = 0.001], and were significantly more likely to have measurable AAA [31% vs 17%, p = 0.001]. Adalimumab concentrations were lower in patients with detectable AAA compared with those without [3.59 µg/mL vs 12.0 µg/mL, p < 0.001]. Adalimumab was not detected in fecal samples. Adalimumab serum concentrations were lower in obese patients compared with in non-obese patients [p = 0.046]. Adalimumab concentration in patients treated with adalimumab to prevent symptomatic endoscopic recurrence postoperatively is, for most patients, well within the therapeutic window, and is not significantly lower in patients who develop recurrence compared with in those who remain in remission. Mechanisms of anti-TNF failure to prevent postoperative recurrence remain to be determined in these patients.

Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn's disease.

Background:Low anti-tumor necrosis factor α (TNFα) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNFα drug concentrations in patients with inflammatory bowel disease and investigated whether or not subtherapeutic drug concentrations were associated with increased levels of disease activity.Methods:In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn’s disease who were receiving infliximab or adalimumab maintenance therapy. Demographic data, disease activity symptom scores (Partial Mayo Score, Harvey Bradshaw Index), inflammatory markers [C-reactive protein (CRP), fecal calprotectin], antidrug antibodies and serum drug concentrations were recorded. Therapeutic drug concentrations were defined as 3–8 mg/liter for infliximab and 5–12 mg/liter for adalimumab.Results:Of 210 patients included, 137 (65.2%) had Crohn’s disease. In the adalimumab group, subtherapeutic drug concentrations were measured in 16.7% of patients with ulcerative colitis and in 27.7% of patients with Crohn’s disease. In the infliximab group, subtherapeutic drug concentrations were found in 23% (ulcerative colitis) and 30.3% (Crohn’s disease) of patients. In Crohn’s disease, subtherapeutic adalimumab concentrations were associated with higher fecal calprotectin and CRP concentrations compared with therapeutic concentrations. Subtherapeutic infliximab concentrations in patients with Crohn’s disease were also associated with higher CRP concentrations compared with therapeutic concentrations.Conclusions:The prevalence of subtherapeutic drug levels ranged from 17% to 30%. In patients with Crohn’s disease, subtherapeutic serum drug concentrations were associated with significantly higher disease activity with both anti-TNFα agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054]

The Relationship Between Serum Infliximab and Adalimumab Concentrations and Their Corresponding Anti-drug Antibody Levels: Analysis of over 50,000 Patient Results

The Relationship Between Serum Infliximab and Adalimumab Concentrations and Their Corresponding Anti-drug Antibody Levels: Analysis of over 50,000 Patient Results

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...