Serum Golimumab Concentrations Research Articles

P292 Association of golimumab trough concentrations during maintenance with endoscopic and histologic remission in patients with ulcerative colitis

Abstract Background The aim of this study was to investigate the association of serum golimumab concentrations (SGC) during maintenance therapy in UC with clinical outcomes including endoscopic and histologic healing. Methods This multicentre, cross-sectional cohort study included UC patients who had received at least 5 maintenance doses of golimumab. A colonoscopy was scheduled, and study-specific recto-colonic biopsies were taken for blind central histologic reading. Samples for trough SGC and anti-golimumab antibodies (AGA) were collected on the day of the scheduled golimumab administration closest to the colonoscopy. Definitions: clinical remission = partial Mayo score (PMS) ≤2 with no individual subscore >1, combined clinical-biochemical remission = PMS ≤2 + faecal calprotectin <300 μg/g, endoscopic healing = Mayo endoscopic subscore of 0, deep remission = clinical remission + endoscopic healing, histologic remission = Geboes index ≤2.0, and disease clearance = clinical remission + endoscopic healing + histologic remission. Results Fifty-two patients were included. The overall median SGC was 1.79 µg/ml (interquartile range [IQR] 0.87–2.79). Three patients (5.7%) had undetectable SGC together with positive AGA. With a median of 23 [IQR 15–32] months of golimumab therapy, 46 patients (88%) were in clinical remission, 26 (52%) had combined clinical-biochemical remission, 18 patients (35%) had both endoscopic healing and deep remission, 21 (40%) had histologic remission, and 14 (27%) had disease clearance. Median SGC were significantly higher in patients who were in clinical remission (2.01 versus 0.72 µg/mL, P=0.047) µg/mL, combined clinical-biochemical remission (2.21 versus 1.47 µg/mL, P=0.041), mucosal healing and deep remission (2.52 versus 1.47 µg/mL, P=0.003), histologic remission (2.33 versus 1.50 µg/mL, P=0.02), and disease clearance (2.52 versus 1.70 µg/mL, P=0.009), compared with those not meeting these criteria. (Figure 1) The higher SGC quartiles were associated with higher rates of mucosal healing (P=0.005), and histologic remission (P=0.006). (Figure 2) Receiver-operating characteristic analyses identified SGC thresholds [area under the curve] of 0.85 [0.76], 1.90 [0.65], 2.29 [0.75], and 2.29 [0.72] µg/mL be associated with clinical remission, combined remission, deep remission, and disease clearance, respectively. (Table 1) On multivariate analysis, body mass index (P=0.021) and CRP level (P=0.040) were linearly associated with lower SGC, and concomitant immunosuppressant with higher SGC (P=0.47). (Table 2) Conclusion We identified SGC thresholds during maintenance most closely associated with clinical outcomes including endoscopic and histologic healing. Higher SGC are needed to achieve increasingly stringent therapeutic targets.

Serum golimumab concentration and anti-drug antibodies are associated with treatment response and drug survival in patients with inflammatory joint diseases: data from the NOR-DMARD study

Objectives: This study aimed to identify the therapeutic target concentration and frequency of anti-drug antibodies (ADAbs) in golimumab-treated patients with inflammatory joint disease (IJD). Method: Associations between golimumab concentration, ADAbs, and treatment response were examined in 91 patients with IJD [41 axial spondyloarthritis (axSpA), 20 rheumatoid arthritis (RA), and 30 psoriatic arthritis (PsA)] included in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement in axSpA, European League Against Rheumatism (EULAR) good/moderate response in RA, and improvement of ≥ 50% in modified Disease Activity index for PSoriatic Arthritis (DAPSA) (28 swollen/tender joint counts) in PsA. Serum drug concentrations and ADAbs were analysed using automated in-house assays. Results: At inclusion, 42% were biological disease-modifying anti-rheumatic drug naïve and 42% used concomitant synthetic disease-modifying anti-rheumatic drug. The median golimumab concentration was 2.2 (interquartile range 1.0–3.5) mg/L. The proportions of responders after 3 months among patients with golimumab concentration < 1.0, 1.0–3.9, and ≥ 4.0 mg/L were 19%, 49%, and 74%, respectively. A higher rate of treatment discontinuation was seen in patients with serum golimumab concentration < 1.0 compared to ≥ 1.0 mg/L (hazard ratio 3.3, 95% confidence interval 1.8–6.0, p < 0.05). ADAbs were detected in 6%, and were associated with lower drug concentrations and both reduced treatment response and drug survival. Conclusions: Golimumab concentrations ≥ 1.0 mg/L were associated with improved treatment response and better drug survival, although some patients may benefit from higher concentrations. This study suggests a rationale for dosing guided by therapeutic drug monitoring in golimumab-treated patients with IJD. The results should be confirmed in larger studies including trough samples, and the efficacy of such a strategy must be examined in randomized controlled trials.

FRI0536 SERUM GOLIMUMAB CONCENTRATIONS AND ANTI-DRUG ANTIBODIES ARE ASSOCIATED WITH TREATMENT RESPONSE AND DRUG SURVIVAL IN PATIENTS WITH INFLAMMATORY JOINT DISEASES: DATA FROM THE NOR-DMARD STUDY

Background:Lack or loss of response to TNFα-inhibitors can be caused by subtherapeutic drug levels and anti-drug antibodies (ADAb). Knowledge about associations between clinical efficacy and drug levels as well as occurrence of ADAb is limited in patients with inflammatory joint diseases (IJD) treated with golimumab.Objectives:To identify the therapeutic target concentration and assess the frequency of ADAb in golimumab-treated patients with IJD.Methods:91 patients from the NOR-DMARD study with a clinical diagnosis of axial spondyloarthritis (n=41), rheumatoid arthritis (n=20) or psoriatic arthritis (n=30) starting treatment with golimumab, with an available biobank sample at 3 months follow-up, were included. Treatment response was defined by ASDAS Clinically important improvement in axial spondyloarthritis, EWULAR good/moderate response in rheumatoid arthritis and improvement of ≥50% in modified DAPSA (using 28 swollen/tender joint counts) in psoriatic arthritis. Serum drug concentrations were analysed in non-trough samples collected 3 months after treatment initiation, using an automated in-house target-based immunofluorometric assay. ADAb was measured with an inhibition assay that measures neutralising antibodies. The association between drug levels and treatment response was assessed by multivariable logistic regression (adjusted for age, sex and prior bDMARD (Y/N)). Drug-survival was assessed by Kaplan-Meier curves and Cox proportional hazard regression analysis.Results:Golimumab serum concentrations varied considerably between patients on standard dose (range 0.0-8.2 mg/L) with a median of 2.2 (IQR 1.0-3.5) mg/L. The proportions of responders after 3 months among patients with golimumab concentration &lt;1.0, 1.0-3.9 and ≥4.0 mg/L, were 19%, 49% and 74%, respectively (Fig.1). The likelihood of response after 3 months of treatment was significantly higher among patients with serum golimumab concentration ≥1.0 mg/L compared to those with golimumab &lt;1.0 mg/L (OR 5.8 (95% CI 1.7-19.7), P =0.005). The proportion of responders was highest among patients with golimumab concentrations ≥4.0 mg/L, but the difference in response between patients with concentrations ≥4.0 mg/L compared to 1.0-4.0 mg/L was not statistically significant (OR 2.1 (95% CI 0.6-7.1), P=0.24). We also found a higher rate of treatment discontinuation in patients with serum golimumab concentration &lt;1.0 mg/L compared to ≥1.0 mg/L (HR 3.6 (95% CI 1.9-6.9), P &lt;0.001) (Fig.2). ADAb were detected in 5 of 91 samples and were associated with lower drug concentrations. Only 1 out of 5 ADAb-positive patients was a responder at 3 months, and all 5 ADAb positive patients discontinued treatment within the first 14 months.Conclusion:Golimumab concentrations ≥1.0 mg/L were associated with improved treatment response and better drug survival, but our results also indicate that some patients might benefit from higher concentrations. ADAb were associated with lower drug concentrations and both reduced treatment response and drug survival. These findings suggest a rationale for personalised dosing guided by measurements of drug concentration and ADAb in golimumab-treated patients with IJD, which should be addressed in future randomised strategy trials.Disclosure of Interests:Johanna Elin Gehin Speakers bureau: Roche, David J Warren: None declared, Silje Watterdal Syversen Speakers bureau: Roche, Thermo Fisher, Elisabeth Lie: None declared, Joe Sexton: None declared, Liz Loli: None declared, Ada Wierød: None declared, Trine Bjøro: None declared, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Nils Bolstad Consultant of: Pfizer, Janssen, Speakers bureau: Orion Pharma, Napp Pharmaceuticals, Takeda, Roche, Novartis, Guro Løvik Goll Consultant of: Novartis, Pfizer, Speakers bureau: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCBTable 1.Change in FVC(ml) and DLCO% in the 6–12 months before and after different treatmentTreatment groupPre-TxPost-TxpR9.8% (11)FVCDLCO2015±74672.4±17.22024±80360.7±27.90.780.43CYC25.0% (28)FVCDLCO1853±58561.2±23.81796±57861.4±23.90.740.79R+CYC17.9% (20)FVCDLCO1901±66758.2±14.51922±67246.7±18.80.900.90Non-R, CYC47.3% (53)FVCDLCO2177±65746.7±18.82286±70445.8±19.60.470.69SubgroupUIP31.3% (35)FVCDLCO2053±72158.9±22.71949±72749.3±25.10.570.15Non-UIP68.8% (77)FVCDLCO(%)1908±60859.0±18.71961±65460.5±1850.530.46Table 2.Secondary outcome and multivariable Cox model for overall survival

P723 Therapeutic thresholds for golimumab serum concentrations during induction and maintenance: Results from the GO-LEVEL study

Abstract Background The exposure–response relationship associated with the use of golimumab for UC has been previously demonstrated in the PURSUIT trial programme. A significant association between serum golimumab concentrations (SGC) and favourable outcomes was observed during both induction and maintenance therapy. However, data regarding the optimal therapeutic SGC threshold is limited. Methods GO-LEVEL was an open-label, phase IV, investigator initiated study (NCT03124121) which included a prospective cohort of UC patients commencing golimumab induction therapy, as well as a cross-sectional cohort receiving maintenance treatment (&amp;gt;18 weeks from initiation). Patients commencing induction therapy all had disease activity objectively confirmed and were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare, or during stable remission. Clinical disease activity was evaluated using SCCAI and PRO2, and biochemical activity using FC and CRP. Combined clinical-biochemical remission was defined as SCCAI&amp;lt;3 as well as FC&amp;lt;250ug/g. SGC and anti-golimumab antibodies (AGA) were measured using a drug-sensitive ELISA (LISATRACKER, Theradiag). Fishers exact or Mann–Whitney U were used to compare groups, ROC analysis to identify therapeutic thresholds and Spearman’s rank coefficient (rs) for correlations. Results Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined remission at week 6. The median SGC of those in combined remission was significantly higher than those who were not (5.0 vs. 3.1 μg/ml, respectively, p = 0.03). ROC curve analysis demonstrates 3.8 μg/ml as the optimal therapeutic threshold to achieve combined remission at week 6 (sensitivity 0.71, specificity 0.65, AUC 0.72). Significant, inverse correlations were also observed between week 6 SGC and PRO2, CRP and FC (rs −0.41 (p = 0.01), −0.47 (p = 0.004) and −0.40 (p = 0.02), respectively). However, week 6 SGC did not predict outcomes at week 10 or 14. Sixty-four patients were included in the maintenance cohort; 32 (50%) were in combined remission, 32 were not. The median SGC of those in combined remission was significantly higher (3.0 vs. 2.1 μg/ml, respectively, p = 0.003). ROC curve analysis demonstrates 2.4 μg/ml as the optimal therapeutic threshold to achieve combined remission (sensitivity 0.73, specificity 0.66, AUC 0.71). No AGA were detected in either cohort. Conclusion GO-LEVEL offers further evidence of the exposure-response relationship with golimumab. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested SGC therapeutic thresholds of 3.8 μg/ml at week 6 and 2.4 μg/ml during maintenance.

Population Pharmacokinetics and Exposure–Response Modeling of Golimumab in Adults With Moderately to Severely Active Ulcerative Colitis

PurposeGolimumab is a fully human monoclonal antibody to tumor necrosis factor-α and is indicated for the treatment of moderately to severely active ulcerative colitis (UC). This study analyzed the population pharmacokinetic (PK) properties of golimumab and exposure–response for efficacy and safety, using data from combined Phase II/III UC studies. MethodsData on serum golimumab concentration following IV and subcutaneous (SC) administration were fitted simultaneously using nonlinear mixed-effects modeling for the development of a population PK model. Logistic regression models were used for assessing relationships between serum golimumab concentrations and clinical efficacy outcomes in SC induction and maintenance studies. The percentages of patients developing infections, serious infections, and serious adverse events were assessed by golimumab exposure metric quartiles. FindingsThe PK properties of golimumab are well described by a 2-compartment model with first-order absorption and elimination. Typical values of PK parameters in a 70-kg patient were clearance, 0.544 L/d; central and peripheral compartment Vd, 3.43 and 2.27 L, respectively; and intercompartmental clearance, 0.291 L/d. Golimumab t1/2 was 10.5 days; bioavailability following SC administration was 52.2%. Body weight, anti-golimumab antibodies, serum albumin, C-reactive protein, and alkaline phosphatase affected golimumab disposition. A positive exposure–response relationship was established between golimumab concentration and efficacy outcomes. No apparent correlation between golimumab exposure and rate of infections, serious infections, or serious adverse events was observed in patients receiving golimumab 50 or 100 mg SC every 4 weeks through 1 year. ImplicationsBody weight, serum albumin, and anti-golimumab antibodies explain some of the variability observed in the PK properties of golimumab, and exposure–response findings support the recommended posology of golimumab in UC. ClinicalTrials.gov identifiers: NCT00488774, NCT00487539, and NCT00488631.

Early Dose Optimisation of Golimumab in Nonresponders to Induction Treatment for Ulcerative Colitis Is Effective and Supported by Pharmacokinetic Data.

In nonresponders to golimumab induction for ulcerative colitis, we assessed clinical response rates and golimumab serum concentrations when the 100-mg dose was used early in the course of maintenance. This post-hoc analysis of golimumab maintenance dosing [in the PURSUIT-M study] examined clinical outcomes and golimumab concentrations in early [Week 6] responders and nonresponders to induction, including subgroups based on body weight. In nonresponders to golimumab induction [assessed at Week 6], the 100-mg maintenance dose [starting at Week 6] resulted in a meaningful proportion [28.1%] of patients achieving a partial Mayo response at Week 14. After 1 year of maintenance, clinical outcome [response, remission, mucosal healing, corticosteroid-free state] rates in these "late" [Week 14] responders were similar to those in early [Week 6] responders. Golimumab concentrations in early nonresponders were approximately half those of early responders, suggesting that early nonresponders had more rapid golimumab clearance. Examined by body weight, the early nonresponders weighing <80 kg and receiving 100 mg had golimumab concentrations similar to the early responders [weighing <80 kg or ≥80 kg and receiving 50 mg or 100 mg, respectively]. Early use of the 100-mg maintenance dose leads to positive clinical outcomes in a meaningful proportion of patients who did not respond to golimumab at Week 6. Early nonresponders <80 kg who received the 100-mg maintenance dose achieved adequate golimumab concentrations and a clinically meaningful proportion of these patients had a late clinical response.PURSUIT-M protocol number C0524T18; ClinicalTrials.gov, NCT00488631; EudraCT, 2006-003399-37.

Immunogenicity of Golimumab and its Clinical Relevance in Patients With Ulcerative Colitis.

Antidrug antibody (ADA) detection with standard bridging enzyme immunoassays (EIA) can yield false-negative results or underestimate titers through drug interference. A more sensitive assay was needed to determine clinical impact of antigolimumab antibodies. A high-sensitivity, drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original EIA, and samples from induction/maintenance studies in golimumab-treated patients with ulcerative colitis were analyzed for ADAs using both methods. Immunogenicity results were compared, and pharmacokinetic, efficacy, and safety associations were evaluated. An 8-fold increase in ADA-positive patients (21.8% DT-EIA vs 2.8% EIA) reflected DT-EIA improved sensitivity and drug tolerance. Most newly detected ADA-positive patients (using DT-EIA) had low antibody titers, whereas most with high antibody titers were ADA-positive with original EIA. With DT-EIA, week 44 median trough serum golimumab concentrations among ADA-positive patients were approximately half vs ADA-negative (0.51 vs 0.85 µg/mL [50 mg q4w]; 0.85 vs 1.60 µg/mL [100 mg q4w]). Antidrug antibody impact on golimumab concentrations was more notable at titers ≥1:100. During induction, ADAs had no notable impact on efficacy. During maintenance, proportions of patients maintaining clinical response through week 54 were lower using DT-EIA: 38.1% ADA-positive and 52.8% ADA-negative. Antidrug antibody status had no impact on injection-site reaction incidence. A more sensitive DT-EIA identified higher proportions of ADA-positive patients. A trend of decreasing drug concentrations with increasing ADA titers was observed. Pharmacokinetic impact was better elucidated with DT-EIA. Although development of ADA did not preclude efficacy, a trend toward decreased efficacy in ADA-positive vs ADA-negative patients was observed during maintenance treatment. Antidrug antibody status did not impact safety.

P683 Higher serum golimumab concentrations are significantly associated with combined clinical-biochemical remission during maintenance therapy: results from the GO-LEVEL study

P683 Higher serum golimumab concentrations are significantly associated with combined clinical-biochemical remission during maintenance therapy: results from the GO-LEVEL study

Population Pharmacokinetics and Exposure-Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis.

Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to compare the PK and E-R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6-17years) in the PURSUIT-PEDS-PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2-17years) in the GO-KIDS study, were included in the population PK analysis. E-R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score-based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1-compartment model with first-order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model-estimated terminal half-life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT-PEDS-PK may be needed for children ≤45kg to achieve exposures comparable to adults. Comparable E-R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E-R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population.

Immunogenicity of golimumab and its clinical relevance in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Golimumab immunogenicity was extensively studied during clinical development. As anti-drug antibody (ADA) detection with the standard bridging EIA (original-EIA) can yield false-negative results or underestimate ADA incidence and titres due to drug interference, a more sensitive assay was needed to determine clinical impact. A highly sensitive drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original-EIA. Samples from phase-3 subcutaneous golimumab rheumatological trials (GO-FORWARD-rheumatoid arthritis, GO-REVEAL-psoriatic arthritis, GO-RAISE-ankylosing spondylitis) were then retested. Associations between ADAs and golimumab pharmacokinetics, efficacy and safety were assessed. The DT-EIA was more sensitive than the original-EIA and capable of detecting ADAs amid golimumab concentrations far exceeding those in immunogenicity test samples. Consequently, an 8-fold increase in the incidence of ADAs was observed with the DT-EIA (31.7%) vs original-EIA (4.1%) in the studies. Most ADA-positive patients identified by the DT-EIA had lower antibody titres, while most with higher titres were previously identified as ADA-positive by the original-EIA. With the DT-EIA, ADA-positive patients generally had lower trough serum golimumab concentrations than ADA-negative patients; however, ADA impact on serum golimumab concentrations was more notable at higher ADA titres (⩾100). No impact of ADAs on clinical efficacy or injection-site reactions was evident. ADA incidence was expectedly higher using the DT-EIA vs original-EIA; newly detected ADAs were characterized mostly by low titres, with no impact on clinical efficacy or injection-site reactions, consistent with previously observed original-EIA results. Golimumab immunogenicity with the DT-EIA is consistent with existing knowledge regarding the clinical relevance of ADAs detected with the original-EIA in patients with rheumatological disorders. NCT00264550, NCT00265096, NCT00265083.

Long-Term Benefit of Golimumab for Patients with Moderately to Severely Active Ulcerative Colitis: Results from the PURSUIT-Maintenance Extension.

To evaluate the safety and efficacy of 3 additional years of subcutaneous golimumab maintenance in patients with moderately to severely active ulcerative colitis. The PURSUIT-maintenance long-term extension enrolled patients who had completed placebo or golimumab 50 mg or 100 mg treatment every 4 weeks [q4w] through Week 52 and evaluations at Week 54 [n = 666]; treatment continued through Week 212. Patients receiving placebo were discontinued after study unblinding. Efficacy endpoints, golimumab concentrations, and anti-drug antibodies were summarized as observed for golimumab-induction responders who continued golimumab therapy during the long-term extension. Observations relating to safety were summarized for all treated patients. Overall, 63% of patients who were receiving golimumab at the beginning of the extension remained on treatment through the end of the study. Among all treated patients in the extension, rates of adverse events of special interest [e.g. tuberculosis, demyelination, and malignancy] were infrequent. Nine deaths occurred during the extension [1 placebo, 1 golimumab 50 mg, and 7 golimumab 100 mg]. Serum golimumab concentrations were dose-proportional and were maintained over time. During the extension through Week 228, anti-drug antibody rates with golimumab 50 mg and 100 mg were 4.4% and 3.7%, respectively. Among golimumab-induction responders, 99.3% had no disease or mild disease activity as per the Physician's Global Assessment, 92.5% were corticosteroid-free, and 76.1% had an Inflammatory Bowel Disease Questionnaire score of ≥170 at Week 216. Subcutaneous golimumab treatment of moderately to severely active ulcerative colitis for up to 3 additional years during the extension maintained clinical benefit with no new safety signals observed.ClinicalTrials.gov number NCT00488631.

Golimumab for moderate to severe ulcerative colitis

ABSTRACTIntroduction: Golimumab (GLM) is a subcutaneously administered human anti-tumor necrosis factor (TNF) agent that has been approved by the regulatory authorities for the treatment of moderate to severe ulcerative colitis (UC) in 2013.Areas covered: Maintained clinical remission rates up to 50% have been shown in UC patients receiving GLM, and higher GLM serum concentrations have been associated with improved clinical outcomes. Approximately 50% of UC patients do not respond to induction therapy with GLM, and up to 40% of GLM responders will lose response over time. In most patients, loss of response is associated with low serum GLM concentrations, which suggests insufficient exposure to GLM. Low GLM serum concentrations may be avoided by therapeutic drug monitoring.Expert commentary: So far, the therapeutic window for GLM has not yet been defined, but options to dose increase GLM based on therapeutic drug monitoring might result in improved clinical outcome and higher success rates.

P226 Comparison of four different immunoassays for measuring golimumab and anti-golimumab antibody concentration in patients with ulcerative colitis

Background: Golimumab is an anti-TNF antibody with higher affinity for TNF compared to infliximab and adalimumab and higher stability compared to infliximab1. The PURSUIT trials showed a significant exposure-response relationship with golimumab in ulcerative colitis (UC). Low drug exposure may be related to primary and secondary non-response as described for infliximab and adalimumab. To assess if assay results obtained with different methods can be considered comparable, we conducted a comparison of different immunoassays measuring levels of golimumab and anti- drug antibodies (ADA). Methods: We included serum samples from 80 patients with UC recruited in an ongoing prospective observational study who started on golimumab treatment. Golimumab was quantified by either an anti-IgG detection antibody (Theradiag) or an antibody directed against the idiotype of golimumab (Sanquin and KU Leuven, Janssen R&D). Bridging drug-sensitive ELISA assays (Theradiag, Janssen R&D, KU Leuven), a bridging drug-tolerant ELISA assay (Janssen R&D), and a radioimmunoassay (Sanquin) were used to quantify ADA. Results: Median (IQR) serum golimumab levels were 4.5 (2.2–6.6), 3.5 (1.7–4.8), 4.9 (2.6–7.0), and 2.4 (1.2–4.0) μg/mL with Theradiag, Sanquin, KU Leuven and Janssen R&D assays, respectively. Median assay values are different between assays in head to head comparisons (p=0.0001), except for comparison of median levels between Theradiag and KU Leuven (p=0.155) and comparison of Sanquin and Janssen R&D assay values (p=0.055). With the Sanquin and Leuven assays, 84% of samples are in the same quartile of distribution of values; this overlap was 71% for Sanquin and Theradiag, 66% for Theradiag and Leuven assays, 68% for Theradiag and Janssen R&D, 81% for Leuven and Janssen R&D and 86% for Sanquin and Janssen R&D. All but not the Theradiag assays showed specificity for golimumab as these make use of an anti-idiotype antibody to golimumab for detection. We were not able to compare ADA concentrations determined by the different assays. However, ADA were detected in the two same patients by Theradiag, Sanquin and KU Leuven assays and in one of those two with the drug-sensitive Janssen R&D assay. ADA were detected in 27.5% of samples (22/80) with the Janssen R&D drug-tolerant assay. Table 1. Correlation between assays to measure Golimumab serum levels Conclusions: There is an acceptable correlation between golimumab serum concentrations measured with Theradiag, Sanquin, KU Leuven and Janssen R&D assays. The low number of ADA positive samples precludes statistical concordance between ADA values measured with the different assays.

Pharmacokinetics and Exposure-response Relationship of Golimumab in Patients with Moderately-to-severely Active Ulcerative Colitis: Results from Phase 2/3 PURSUIT Induction and Maintenance Studies

Although tumour necrosis factor-α [TNF] antagonists have revolutionized therapy for ulcerative colitis [UC], challenges still remain. Even today a significant proportion of patients fail induction therapy [primary non-responders] and many others develop a secondary loss of response over time. Since treatment options to induce remission in patients with UC increase, the issue of selecting the right drug and the correct dose ensues. Therapeutic drug monitoring [TDM] and subsequently dose optimization based on drug serum concentrations has proven to maximize treatment efficacy for infliximab and adalimumab. Golimumab is the most recently marketed anti-TNF biological available to treat patients with moderate-to-severe UC. At this moment, little is known about the benefit of measuring golimumab serum concentrations in daily practice and how it could affect clinical management of individual patients. A small observational study provided first evidence that golimumab concentrations are associated with clinical response.1 This issue by Adedokun et al. 2 provides additional data on the relation between golimumab serum concentrations and efficacy outcomes, as well as on the factors influencing it. Using a large UC cohort of 1064 patients, the authors showed that steady state was reached approximately 8 weeks after golimumab maintenance commenced [Week 14] and that trough concentrations were dose-proportional, with higher efficacy response rates during both … Corresponding author: Ann Gils, PharmD, PhD, Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, ON fax: +32 16 32 34 60; email: ann.gils{at}pharm.kuleuven.be

Variability in Golimumab Exposure: A 'Real-Life' Observational Study in Active Ulcerative Colitis.

Golimumab has been approved recently to treat refractory moderate-to-severe ulcerative colitis [UC]. To date it is not clear why a considerable fraction of patients do not respond, or lose initial response, to golimumab therapy. Our aim was to investigate whether a low golimumab serum concentration and/or a positive anti-golimumab antibody status reduces the efficacy of this drug in patients with UC. Serum samples of 21 patients with moderate-to-severe UC were collected during the first 14 weeks of golimumab therapy. For measurement of golimumab serum concentrations, both a tumour necrosis factor [TNF]-coated enzyme-linked immunosorbent assay [ELISA] and a sandwich-type ELISA were developed. Anti-golimumab antibodies were measured using a bridging ELISA and a newly-developed drug-tolerant immunoassay. Clinical response and mucosal healing were assessed 14 weeks after start of treatment. Out of 21 patients, 10 [48%] reached partial clinical response at Week 14. Median [interquartile range] serum golimumab concentration was significantly higher in partial clinical responders than in non-responders: 10.0 [7.8-10.5] µg/ml versus 7.4 [4.8-8.3] µg/ml at Week 2 [p = 0.035] and 5.1 [4.0-7.9] µg/ml versus 2.1 [1.8-4.2] µg/ml at week 6 [p = 0.037]. Four out of 21 UC patients developed anti-golimumab antibodies, detectable only using a drug-tolerant immunoassay, and three had a partial clinical response at that time. Clinical non-responders had a significantly more severe colitis, indicated by a higher endoscopic Mayo score at baseline compared with partial clinical responders [p = 0.048]. Adequate exposure to golimumab drives clinical response. A worse disease at baseline influences clinical response rate negatively.

A36: Long‐term Pharmacokinetics of Body Surface Area‐Adjusted Doses of Golimumab Following Repeated Subcutaneous Administrations in Pediatric Patients With Polyarticular Juvenile Idiopathic Arthritis

Background/Purpose:To assess the pharmacokinetics (PK) and PK‐efficacy correlations of body surface area (BSA)‐adjusted dosing of 30 mg/m2 golimumab administered subcutaneously (SC) every 4 weeks (q4w) + methotrexate (MTX) through Week 48 in pediatric patients (ages 2 to &lt;18 years) with juvenile idiopathic arthritis (JIA).Methods:GO‐KIDS is a randomized‐withdrawal, double‐blind, placebo‐controlled, parallel‐group, multicenter Phase 3 trial of SC golimumab 30 mg/m2 (maximum 50 mg) q4w + MTX (10/N30 mg/m2/week) in pediatric patients with active JIA despite current MTX therapy (median 15 mg/week). PK, safety, and efficacy evaluations were performed q4w through week 16. At Week 16, patients who were ACR JIA 30 responders were randomized (1:1) to 30 mg/m2 golimumab or placebo q4wks through Week 48 with GLM reinstituted upon flare (defined as per JIA ACR flare criteria) or initiation of new DMARDS, biologics, systemic immunosuppressives. Serum trough concentrations were also obtained at Weeks 12, 16, 24 and 48. Serum golimumab trough concentrations for 154 patients were determined via a validated immunoassay. The relationships of ACR pediatric 30 response and disease flare status with steady‐state trough levels at Week 48 were assessed.Results:Trough serum golimumab concentrations in patients receiving SC 30 mg/m2 golimumab q4w through Week 48 were maintained over time. Steady‐state trough golimumab levels were similar across different age groups, and were also similar to those seen in adult RA patients who received 50 mg SC q4w in Phase III clinical trials. There were no apparent differences in pediatric ACR JIA 30 response rates and disease flare rates among the 4 groups of JIA patients categorized by the 4 quartiles of steady‐state trough golimumab levels at Week 48. In addition, there were no apparent PK differences between patients who did and did not experience disease flares in the randomized golimumab group. Mean (SD) and median trough serum golimumab concentrations (mg/mL) by age groups and body weight quartiles are presented in the . Age Groups (Years) 2–6 ≥6 to 12 ≥12 Combined Week 12 Mean (SD) 1.42 (0.744) 0.95 (0.593) 1.21 (0.711) 1.14 (0.685) Median 1.77 0.92 1.29 1.46 Week 16 Mean (SD) 1.17 (0.650) 0.96 (0.721) 1.24 (0.836) 1.13 (0.780) Age Groups (Years) 2–6 ≥6 to 12 ≥12 Combined Median 1.22 0.89 1.23 1.10 Week 24 Mean (SD) 1.30 (0.833) 1.08 (0.876) 1.23 (1.003) 1.19 (0.927) Median 1.57 1.12 1.08 1.12 Week 48 Mean (SD) 0.86 (0.574) 0.95 (0.715) 1.19 (0.777) 1.08 (0.736) Median 0.87 0.73 1.25 0.95 Body Weight Quartiles (kg) ≤15.60 &gt;15.60 to ≤18.60 &gt;18.60 to ≤21.90 &gt;21.90 Week 12 Mean (SD) 1.09 (0.723) 1.09 (0.622) 1.54 (0.649) 0.90 (0.642) Median 1.13 1.09 1.49 0.83 Week 16 Mean (SD) 0.99 (0.622) 1.07 (0.739) 1.60 (0.845) 0.99 (0.806) Median 0.90 1.12 1.76 0.89 Week 24 Mean (SD) 0.91 (0.799) 1.38 (0.780) 1.52 (1.243) 1.05 (0.844) Median 0.61 1.37 1.42 1.00 Week 48 Mean (SD) 0.74 (0.468) 1.22 (0.852) 1.59 (0.498) 0.94 (0.789) Median 0.75 1.10 1.55 0.81Conclusion:Treatment with 30 mg/m2 SC golimumab q4w + MTX resulted in sustained steady‐state trough serum golimumab concentrations over time. The PK/efficacy correlation analyses demonstrated that the BSA‐adjusted dosing regimen of 30 mg/m2 SC golimumab q4w provided adequate drug exposure for the desired efficacy.

Pharmacokinetics and Safety of Golimumab in Healthy Chinese Subjects Following a Single Subcutaneous Administration in a Randomized Phase I Trial

Golimumab is an anti-tumor necrosis factor-α human immunoglobulin G1κ monoclonal antibody that is efficacious for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in adults. The objective of this study was to assess the pharmacokinetic characteristics of golimumab in healthy male Chinese subjects following a single subcutaneous (SC) administration of golimumab 50 or 100 mg. The safety, tolerability, and immunogenicity of a single SC administration of golimumab in Chinese subjects were also evaluated. This was a phase I, randomized, open-label, single-dose, single-period, single-center study. Twenty-four healthy male Chinese subjects were randomized (1:1) to receive a single SC administration of golimumab 50 or 100 mg. Serial blood samples for the measurement of serum golimumab concentrations were collected and analyzed using a validated electrochemiluminescent immunoassay method. The pharmacokinetic parameters [maximum observed serum concentration (C(max)), time to reach C(max) (t(max)), area under the serum concentration-time curve from time zero to infinity (AUC∞), and terminal half-life (t(½))] of golimumab were derived using a noncompartmental analysis. Following a single SC administration of golimumab 50 or 100 mg in Chinese male subjects (age 19-41 years, body weight 60-76 kg), mean ± standard deviation C(max) (3.6 ± 1.6 and 7.5 ± 1.4 μg/mL, respectively) and AUC∞ (59.8 ± 19.8 and 132.8 ± 27.0 μg·day/mL, respectively) increased in a dose-proportional manner. The median t(max) was in the range of 4.5-5.0 days, and the mean t(½) was in the range of 10.8-11.9 days. Among 24 subjects, 23 had appropriate samples for evaluation of antibodies to golimumab, and one subject (1/23, 4.3%) in the 100-mg group tested positive. Three mild adverse events were reported (infected sebaceous cyst, upper respiratory tract infection, and headache), all in the 50-mg group; none were considered to be related to the study agent. Golimumab exhibited linear pharmacokinetics at dose levels of 50 and 100 mg following a single SC administration in healthy Chinese subjects. Single SC administrations of golimumab 50 or 100 mg were considered to be generally well tolerated. The results from this study indicate that there are no apparent ethnic differences in the pharmacokinetics of golimumab between Chinese and Caucasian subjects.

FRI0176 Golimumab, a human anti-TNF monoclonal antibody, administered subcutaneously every four weeks as monotherapy in patients with active rheumatoid arthritis despite dmard therapy: 52-week results of clinical, radiographic and pharmacokinetic assessments

ObjectivesTo assess the efficacy and safety of golimumab (GLM) as monotherapy in Japanese patients (pts) with active rheumatoid arthritis (RA) despite DMARD therapy.MethodsGO-MONO is a multicenter, randomized, double-blind, placebo (PBO)-controlled...

Golimumab Pharmacokinetics After Repeated Subcutaneous and Intravenous Administrations in Patients with Rheumatoid Arthritis and the Effect of Concomitant Methotrexate: An Open-Label, Randomized Study

BackgroundThe pharmacokinetics of golimumab, a human monoclonal antibody that inhibits the activity of tumor necrosis factor α, after a single subcutaneous (SC) or intravenous (IV) administration have been previously studied. ObjectivesThe purpose of this study was to assess the pharmacokinetics of golimumab after multiple SC or IV administrations in patients with active rheumatoid arthritis (RA). The effect of concomitant methotrexate (MTX) use on golimumab pharmacokinetics was evaluated. MethodsIn this open-label, randomized, Phase I study, 49 adult patients with RA received SC golimumab 100 mg (n = 33) every 4 weeks through week 20 or IV golimumab 2 mg/kg (n = 16) at weeks 0 and 12. Serial blood samples were collected, and serum golimumab concentration was measured with an electrochemiluminescent immunoassay. Golimumab pharmacokinetic parameters were derived with the use of a noncompartmental analysis. Adverse events were monitored at every visit. ResultsThe population was predominantly Caucasian (84%) and female (76%), and the median age was 57 years. After SC golimumab administration, the serum golimumab concentration achieved steady state by ∼12 weeks with mean trough serum concentrations ranging from 1.15 to 1.24 μg/mL. After the final 30-minute IV infusion of golimumab 2 mg/kg, the mean (SD) clearance (CL) was 7.5 (2.6) mL/d/kg. The mean terminal half-life after SC and IV administrations was ∼13 days. The mean absolute bioavailability for SC golimumab was estimated to be 53%. The geometric mean of golimumab CL/F in patients with and without concomitant MTX use was 13.9 and 21.2 mL/d/kg, respectively, and the geometric mean ratio of CL/F was 65.5% (90% CI: 45.2%–94.9%, P = 0.06). Golimumab was generally well tolerated. No malignancies or deaths occurred during the study. ConclusionsPharmacokinetics of golimumab were consistent after SC or IV administration in this population of patients with RA. Golimumab was well tolerated and no unexpected adverse events were observed in this trial. ClinialTrials.gov identifier: NCT01362153.

Subcutaneous Bioavailability of Golimumab at 3 Different Injection Sites in Healthy Subjects

This study characterized the pharmacokinetics (PK) of golimumab, an antitumor necrosis factor alpha human IgG1kappa monoclonal antibody, after a single intravenous (IV) or subcutaneous (SC) administration in healthy subjects and determined the absolute bioavailability of SC golimumab delivered at 3 different anatomical regions. Seventy-eight healthy adult males were randomly assigned to receive a single dose of golimumab 100 mg by IV (30-minute infusion, n = 23) or SC administration at different sites (upper arm, n = 18; abdomen, n = 18; thigh, n = 19). Serial blood samples were collected for PK characterization. Following IV administration, the mean maximum observed serum golimumab concentration (C(max)) and the mean area under the concentration versus time curves from time zero to infinity (AUC(0-infinity)) were 29.5 +/- 5.8 microg/mL and 195.9 +/- 48.9 microg x d/mL, respectively. After SC administration, the mean values of C(max) and AUC(0-infinity) were 6.3 +/- 2.8 microg/mL and 100.1 +/- 29.2 microg x d/mL, respectively. The median terminal half-life was similar for SC and IV administration (10.9 and 11.8 days, respectively). The overall mean bioavailability of SC golimumab was 51%, and absorption was similar for the 3 injection sites. Golimumab 100 mg was generally well tolerated in this study. Results support the flexibility in the choice of an injection site for SC administration of golimumab.