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Background and Aims The Phase 3 study ENVISION I demonstrated efficacy and safety of adalimumab in paediatric patients with moderate to severe ulcerative colitis. The protocol-specified high-dose adalimumab regimen was numerically more efficacious than the standard-dose regimen. The objective of this work was to bridge a fixed-dosing regimen to the protocol-specified high-induction/high-maintenance, body weight-based dosing regimen studied in ENVISION I, using a pharmacometrics modelling and simulation approach. Methods A stepwise strategy was implemented, including developing an adalimumab paediatric population pharmacokinetic model; using this model to determine a fixed-dosing regimen in paediatric ulcerative colitis patients which achieves similar concentrations to those observed in ENVISION I patients; determining adalimumab exposure-response relationship using population pharmacokinetic/pharmacodynamic model and data from ENVISION I; simulating clinical remission rate in paediatric ulcerative colitis patients using the Markov exposure-response model and the dosing regimen determined to provide similar efficacy to that observed in ENVISION I. Results Both developed population pharmacokinetic and pharmacokinetic/pharmacodynamic models adequately described the observed data. Adalimumab exposure was identified as a significant predictor of clinical remission at Week 8 based on logistic regression [p Conclusions The population pharmacokinetic/pharmacodynamic model supports the appropriateness of the use of the fixed-dosing regimen in the paediatric ulcerative colitis population.

Background and Aims The efficacy and safety of adalimumab for induction and maintenance of clinical remission in patients with moderately to severely active ulcerative colitis were demonstrated in the ULTRA 1 and 2 clinical trials. This post-hoc, pooled analysis evaluated early changes in laboratory parameters, Mayo subscores, mucosal healing, and health-related quality of life. Methods Mean changes in laboratory parameters including albumin, high-sensitivity C-reactive protein, total protein, haematocrit, haemoglobin, red blood cell and platelet counts, Inflammatory Bowel Disease Questionnaire, and Short Form 36 Health Survey were evaluated from baseline to Weeks 4 and 8. Mean changes in Mayo subscores of rectal bleeding and stool frequency were evaluated from baseline to Weeks 2, 4, 6, and 8. Mucosal healing was assessed with endoscopy at baseline and Week 8. Categorical variables were evaluated with the Cochran-Mantel-Haenszel test; continuous variables were evaluated with analysis of covariance and considered significant if p Results Treatment with adalimumab significantly improved laboratory and quality-of-life measures at Weeks 4 and 8 compared with placebo [p Conclusions Adalimumab resulted in rapid improvements in laboratory markers and early reductions in rectal bleeding and stool frequency. Early improvement in quality-of-life scores correlated with the clinical and laboratory findings.

Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis.The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557.93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period.Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis.AbbVie.

Background and Aims Adalimumab has been shown to be more effective than placebo in healing fistulae in adults with moderately to severely active Crohn’s disease. The efficacy and safety of adalimumab in healing fistulae in children/adolescents with Crohn’s disease from the 52-week IMAgINE 1 clinical trial, and its open-label extension IMAgINE 2, are reported. Methods Children/adolescents with perianal fistulae at baseline of IMAgINE 1 were assessed for fistula closure and improvement during IMAgINE 1 [Weeks 0–52] and from Week 0 of IMAgINE 2 [Week 52 of IMAgINE 1] through to Week 240 of IMAgINE 2 using non-responder imputation. Results A total of 36 children/adolescents had fistulae at baseline of IMAgINE 1 and were included in the analysis. Fistula closure and improvement were observed in 44.4% and 52.8%, respectively, at Week 12. Rates of closure and improvement were maintained throughout the analysis period to Week 292. No new safety signals were identified. Conclusions In children/adolescents with moderately to severely active, fistulizing Crohn’s disease, adalimumab induced perianal fistula closure and improvement within 12 weeks of treatment, with rates that were sustained for more than 5 years. The safety profile of adalimumab in patients with fistulae at baseline was similar to that of the overall population in IMAgINE 1/2. ClinicalTrials.gov identifiers: IMAgINE 1 (NCT00409682); IMAgINE 2 (NCT00686374).

Growth failure is common in children with Crohn's disease. The effect of adalimumab (ADA), a fully human antitumor necrosis factor antagonist, on height velocity in pediatric patients with baseline (BL) linear growth impairment in the IMAgINE 1 trial is presented.This analysis included female and male patients with growth potential (bone age ≤13 and ≤14 yr, respectively), with BL Pediatric Crohn's disease Activity Index30, and who failed or were intolerant to conventional therapy. Patients received open-label induction ADA at weeks 0 and 2 by body weight (≥40 kg, 160 and 80 mg and40 kg, 80 and 40 mg). At week 4, patients were randomized to double-blind high (40 or 20 mg for ≥40 kg or40 kg) or low dose (20 or 10 mg for ≥40 kg or40 kg) every other week ADA to week 52. Height velocity z-score was summarized at BL, week 26, and week 52 by patients with BL growth impairment (z-score ≤-1.0) or normal growth (z-score-1.0).ADA therapy significantly improved and normalized growth rate at weeks 26 and 52 in patients with BL growth impairment (median z-score, BL, -3.25; week 26, -0.34; and week 52, 0.21; P0.001 versus BL for both), but not in patients with normal growth. Growth improvement was significantly greater at week 26 in week 4 responders to induction therapy compared with nonresponders (median z-score 0.09 versus -2.92; P = 0.02).ADA treatment resulted in growth rate normalization as early as week 26 in children with moderately to severely active Crohn's disease and growth impairment.

Article first published online 26 January 2017. Supplemental Digital Content is Available in the Text, Background: IMAgINE 1 assessed 52-week efficacy and safety of adalimumab in children with moderate to severe Crohn's disease. Long-term efficacy and safety of adalimumab for patients who entered the IMAgINE 2 extension are reported. Methods: Patients who completed IMAgINE 1 could enroll in IMAgINE 2. Endpoints assessed from weeks 0 to 240 of IMAgINE 2 were Pediatric Crohn's Disease Activity Index remission (Pediatric Crohn's Disease Activity Index ≤ 10) and response (Pediatric Crohn's Disease Activity Index decrease ≥15 from IMAgINE 1 baseline) using observed analysis and hybrid nonresponder imputation (hNRI). For hNRI, discontinued patients were imputed as failures unless they transitioned to commercial adalimumab (with study site closure) or adult care, where last observation was carried forward. Corticosteroid-free remission in patients receiving corticosteroids at IMAgINE 1 baseline, discontinuation of immunomodulators (IMMs) in patients receiving IMMs at IMAgINE 2 baseline, and linear growth improvement were reported as observed. Adverse events were assessed for patients receiving ≥1 adalimumab dose in IMAgINE 1 and 2 through January 2015. Results: Of 100 patients enrolled in IMAgINE 2, 41% and 48% achieved remission and response (hNRI) at IMAgINE 2 week 240. Remission rates were maintained by 45% (30/67, hNRI) of patients who entered IMAgINE 2 in remission. At IMAgINE 2 week 240, 63% (12/19) of patients receiving corticosteroids at IMAgINE 1 baseline achieved corticosteroid-free remission and 30% (6/20) of patients receiving IMMs at IMAgINE 2 baseline discontinued IMMs. Adalimumab treatment led to growth velocity normalization. No new safety signals were identified. Conclusions: Efficacy and safety profiles of prolonged adalimumab treatment in children with Crohn's disease were consistent with IMAgINE 1 and adult Crohn's disease adalimumab trials.

Background: Dose escalation is often recommended for loss of response in anti-TNFα-treated patients with Crohn’s disease (CD). This 52-week phase 3, multicenter study investigated the efficacy and safety of escalation to adalimumab 80 mg every other week (EOW) in Japanese patients with CD who lost response to maintenance adalimumab 40 mg EOW. Methods: Twenty-eight patients aged ≥15 years with moderately to severely active CD who had previously attained and subsequently lost clinical response to maintenance ada limumab received open-label adalimumab 80 mg EOW during weeks 0–50. Loss of response was defined as CD activity index (CDAI) ≥200, increases in CDAI ≥50 from minimum observed value, and C-reactive protein (CRP) ≥1 mg/dL at screening. The primary endpoint was the proportion of patients achieving a CDAI decrease ≥50 (CR-50) from baseline at week 8. Results: At weeks 8 and 52, 75.0 and 57.1% of patients achieved CR-50 and 25.0 and 35.7% achieved clinical remission (CDAI < 150), respectively; median CRP changes from baseline were −0.39 and −0.77 mg/dL, respectively. Most treatment-emergent adverse events were mild to moderate. Conclusions: Adalimumab dose escalation to 80 mg EOW improved CD activity in patients who had lost response to maintenance adalimumab, with no new safety signals. (ClinicalTrials.gov Identifier: NCT01958827.)

Supplemental Digital Content is Available in the Text. Article first published online 7 March 2016., Background: The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Methods: Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW

Background In the IMAgINE 1 study, adalimumab induced and maintained remission of moderate-to-severe Crohn's disease in children. Aim To assess the efficacy, pharmacokinetics, immunogenicity and safety of immunomodulator and adalimumab combination therapy vs adalimumab monotherapy in paediatric patients with Crohn's disease. Methods Patients 6-17 years 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). Results 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. Conclusions 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.

Summary Background Associations between patient-reported outcomes and mucosal healing have not been established in ulcerative colitis (UC). Aim To evaluate relationships of rectal bleeding and stool frequency with mucosal healing and quality of life (QoL) in patients with UC in two Phase 3 studies (ULTRA 1 and 2). Methods Associations of patient-reported rectal bleeding and stool frequency subscores with mucosal healing (Mayo endoscopy subscore = 0 or 0/1) and QoL [inflammatory bowel disease questionnaire (IBDQ)] were assessed in adalimumab-randomised patients (160/80 mg at Weeks 0/2 followed by 40 mg biweekly or weekly) at Weeks 8 (n = 433) and 52 (n = 299), and in patients with mucosal healing [endoscopy subscore = 0 (n = 17); 0/1 (n = 52)] at Weeks 8 and 52. Results At Week 8, the positive predictive values (PPVs) of rectal bleeding subscore = 0, stool frequency subscore = 0 or both scores = 0 for endoscopy subscore = 0/1 were 69%, 84% and 90% respectively; all proportions increased at Week 52. Equivalent PPVs for these subscores in patients with endoscopy subscore = 0 were 26%, 37% and 46% respectively. Among patients with endoscopy subscore = 0 at Week 8, 87% reported no rectal bleeding, while only 29% reported normal stool frequency; these proportions had increased to 94% and 41% respectively, at Week 52. Among patients with mucosal healing, IBDQ scores trended highest for patients with both rectal bleeding and stool frequency subscores = 0. Conclusions Absence of rectal bleeding and normal stool frequency are often predictive of mucosal healing and QoL, but complete normalisation of stool frequency is encountered rarely in patients with mucosal healing.

Contains fulltext : 195625.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To evaluate the safety of adalimumab in pediatric patients who participated in clinical trials of juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and pediatric enthesitis-related arthritis), psoriasis, and Crohn's disease. STUDY DESIGN: This analysis included data from 7 global, randomized, and open-label AbbVie-sponsored clinical trials of adalimumab and their open-label extensions conducted between September 2002 and December 31, 2015 (cutoff date for ongoing studies). Patients who received >/=1 dose of adalimumab subcutaneously were included. Adverse events that occurred after the first dose of adalimumab and up to 70 days (5 half-lives) after the last dose were reported and events per 100 patient-years were calculated. RESULTS: The analysis included 577 pediatric patients, representing 1440.7 patient-years of adalimumab exposure. Across indications, the most commonly reported adverse events (events/100 patient-years) were upper respiratory tract infections (24.3), nasopharyngitis (17.3), and headache (19.9). Serious infections (4.0 events/100 patient-years) were the most frequent serious adverse events across indications; the most commonly reported was pneumonia (0.6 events/100 patient-years). Serious infection rates were 2.7, 0.8, and 6.6 events/100 patient-years in patients with juvenile idiopathic arthritis, psoriasis, and Crohn's disease, respectively. No events of malignancies were reported. One death (accidental fall) occurred in a patient with psoriasis. CONCLUSIONS: The safety profile of adalimumab in pediatric patients with polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis, psoriasis, and Crohn's disease was generally similar across indications; no new safety signals were identified in the treatment of pediatric patients with adalimumab. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00048542, NCT00775437, NCT00690573, NCT01166282, NCT01251614, NCT00409682, and NCT00686374.

Although adalimumab (ADA) has been shown to induce and maintain clinical remission in moderate to severe ulcerative colitis (UC), some patients (pts) may lose initial response and could benefit from dose escalation. We assessed the effect of ADA dose escalation on various outcomes among pts with UC in clinical practice.

Background and Aims Randomised trials have described the benefits of adalimumab [ADA] for ulcerative colitis [UC]; however, few data are available on health-related quality of life [HRQL] and health care costs in clinical practice. Methods InspirADA, a multicentre, prospective study, evaluated the effect of ADA in patients with moderate to severe UC treated according to usual clinical practice. Outcomes assessed were: Simple Clinical Colitis Activity Index [SCCAI] response/remission rates; changes in HRQL; all-cause direct costs; and UC-related direct and indirect costs from baseline to Week 26. Results Data from 463 patients were analysed. At Week 26, 67% (95% confidence interval [CI]: 62%, 71%) of patients achieved response; 48% [95% CI: 44%, 53%] were in remission. For the overall population, significant [all p < 0.001] improvements from baseline to Week 26 were observed for the Short Inflammatory Bowel Disease Questionnaire [SIBDQ] (mean change ± standard deviation [SD]: 17.4 ± 14.5) and the European Quality of Life—5 Dimensions—5 Level [EQ-5D-5L] (index: 0.1 ± 0.2; visual analogue scale [VAS]: 19.5 ± 25.8). Parallel improvements were seen in work productivity [11% absolute decrease in absenteeism; 25% absolute decrease in impairment while working; and 27% absolute decrease in impairment of ability to perform daily activities, all p < 0.001]. Among study completers, cumulative all-cause medical costs and UC-related medical costs were significantly [both p < 0.001] reduced by 59% and 77%, respectively, 6 months after initiation of therapy compared with the preceding 6 months. The safety profile of ADA was consistent with that observed in previous clinical trials. Conclusions ADA therapy in usual clinical practice is effective at improving and maintaining symptomatic control, improving HRQL, and decreasing costs of medical care among patients with UC.

Extraintestinal manifestations (EIMs) are common in patients with ulcerative colitis (UC) and can have a significant impact on patient morbidity and quality of life. We assessed the effect of adalimumab (ADA) therapy on the resolution of EIMs among patients with moderate to severe UC in clinical practice.

Summary Background Patients with moderately-to-severely active ulcerative colitis (UC) are unlikely to continue anti-TNF therapy in the absence of early therapeutic response. Aim To assess week 52 efficacy, safety and benefit/risk balance of adalimumab treatment in patients with moderately-to-severely active UC failing conventional therapy who achieved clinical response at week 8 in the 52-week ULTRA 2 trial. Methods Patients randomised to adalimumab (160/80 mg, week 0/2; 40 mg, every other week thereafter) in ULTRA 2 who achieved clinical response at week 8 per partial Mayo score (Mayo score without endoscopy subscore) were assessed for week 52 clinical remission, clinical response, mucosal healing, steroid-free remission and steroid discontinuation rates, overall and by prior anti-TNF use. Benefit/risk balance for the overall ITT population (regardless of week 8 responder status) was assessed using ‘net efficacy adjusted for risk’ (NEAR) odds ratios. Safety was assessed using adverse event rates. Results Of 248 adalimumab-treated patients, 123 (49.6%) achieved clinical response at week 8. Of these, 30.9%, 49.6%, and 43.1% achieved clinical remission, clinical response, and mucosal healing, respectively, at week 52. Of the week 8 responders using corticosteroids at baseline (N = 90), 21.1% achieved steroid-free remission and 37.8% were steroid-free at week 52. NEAR odds ratios indicated a positive benefit/risk balance for achievement of week 8 and week 52 response or remission without serious adverse events or serious infections. No safety concerns were identified. Conclusions Adalimumab treatment was associated with a positive benefit/risk balance in the overall population of patients with moderately-to-severely active ulcerative colitis in ULTRA 2; early response was predictive of a positive outcome at 1 year (NCT00408629).

We have developed a novel plasmid vector, pEBTetD, for full establishment of doxycycline-inducible protein expression by just a single transfection. pEBTetD contains an Epstein-Barr virus origin of replication for stable and efficient episomal propagation in human cell lines, a cassette for continuous expression of the simple tetracycline repressor, and a cytomegalovirus-type 2 tetracycline operator (tetO2)-tetO2 promoter. As there is no integration of vector into the genome, clonal isolation of transfected cells is not necessary. Cells are thus ready for use 1 week after transfection; this contrasts with 3-12 weeks for other systems. Adequate regulation of protein expression was accomplished by abrogation of mRNA polyadenylation. In northern analysis of seven cDNAs coding for transport proteins, pools of transfected human embryonic kidney 293 cells showed on/off mRNA ratios in the order of 100:1. Cell pools were also analyzed for regulation of protein function. With two transport proteins of the plasma membrane, the on/off activity ratios were 24:1 and 34:1, respectively. With enhanced green fluorescent protein, a 23:1 ratio was observed based on fluorescence intensity data from flow cytometry. The unique advantage of our system rests on the unmodified tetracycline repressor, which is less likely, by relocation upon binding of doxycycline, to cause cellular disturbances than chimera of tetracycline repressor and eukaryotic transactivation domains. Thus, in a comprehensive comparison of on- and off-states, a steady cellular background is provided. Finally, in contrast to a system based on Flp recombinase, the set-up of our system is inherently reliable.

Impairment of the renal dopaminergic pathway has been shown to result in essential hypertension. The Organic Cation Transporter 2, OCT2 (SLC22A2), has been implicated in renal dopamine handling as well as in the inactivation of circulating catecholamines and is supposed to be involved in blood pressure regulation. This study investigated the association of the OCT2 Ala270Ser polymorphism with essential hypertension and its impact on blood pressure status in 607 Caucasian patients who underwent left heart catheterization. Clinical characteristics and diagnosis were recorded and blood pressure was determined by intravascular measurement. A comparison of genotypes revealed that patients with the Ser270 allele were less frequently affected by the clinical diagnosis of hypertension than homozygous carriers of the wild type allele Ala270 (Kruskal Wallis test, p = 0.028). This relation was even more pronounced in the subgroup of patients without diabetes mellitus (Kruskal Wallis test, p = 0.013). In summary, the first data on OCT2 are presented in the context of a candidate gene analysis. The Ala270Ser polymorphism was significantly associated with essential hypertension in the present sample. This study further suggests a function of OCT2 in blood pressure homeostasis and points to the potential role of the transporter in the development of essential hypertension.

Variants of the SLC22A4 gene are associated with susceptibility to rheumatoid arthritis and Crohn's disease. SLC22A4 codes for an integral membrane protein, OCTN1, that has been presumed to carry organic cations like tetraethylammonium across the plasma membrane. Here, we show that the key substrate of this transporter is in fact ergothioneine (ET). Human OCTN1 was expressed in 293 cells. A substrate lead, stachydrine (alias proline betaine), was identified by liquid chromatography MS difference shading, a new substrate search strategy. Analysis of transport efficiency of stachydrine-related solutes, affinity, and Na + dependence indicates that the physiological substrate is ET. Efficiency of transport of ET was as high as 195 μl per min per mg of protein. By contrast, the carnitine transporter OCTN2 from rat did not transport ET at all. Because ET is transported >100 times more efficiently than tetraethylammonium and carnitine, we propose the functional name ETT (ET transporter) instead of OCTN1. ET, all of which is absorbed from food, is an intracellular antioxidant with metal ion affinity. Its particular purpose is unresolved. Cells with expression of ETT accumulate ET to high levels and avidly retain it. By contrast, cells lacking ETT do not accumulate ET, because their plasma membrane is virtually impermeable for this compound. The real-time PCR expression profile of human ETT, with strong expression in CD71 + cells, is consistent with a pivotal function of ET in erythrocytes. Moreover, prominent expression of ETT in monocytes and SLC22A4 polymorphism associations suggest a protective role of ET in chronic inflammatory disorders.

The hypoglycaemic drug tolbutamide is used for assessment of CYP2C9 activity in vivo. However, therapeutically active doses of 500 mg bear the risk of hypoglycaemia, and a tolbutamide-derived parameter based on a single plasma or urine concentration reflecting CYP2C9 activity accurately is lacking.We examined tolbutamide and its metabolites 4'-hydroxy-tolbutamide and carboxytolbutamide in plasma and urine of 26 healthy, male volunteers up to 24 h after intake of 125 mg tolbutamide using liquid chromatography-tandem mass spectrometry. CYP2C9 genotypes were determined by sequencing of exons 3 and 7. Raw plasma and urine data were compared with pharmacokinetic parameters, CYP2C9 genotypes, and data from a study in 23 volunteers with all six CYP2C9*1-*3 combinations who received 500 mg tolbutamide.Plasma clearance and tolbutamide plasma concentrations 24 h after drug intake reflected the genotypes: 0.85 l/h and 1.70 microg/ml (95% confidence interval, CI, 0.80-0.89 l/h and 1.50-1.90 microg/ml) for CYP2C9*1 homozygotes (n=15), 0.77 l/h and 2.14 microg/ml (95%CI, 0.67-0.88 l/h and 1.64-2.63 microg/ml) for *1/*2 genotypes (n=7), 0.60 l/h and 3.13 microg/ml (95%CI, 0.58-0.62 l/h and 2.68-3.58 microg/ml) for *1/*3 genotypes (n=3), and 0.57 l/h and 3.27 microg/ml in the single *2/*2 carrier. Natural logarithms of tolbutamide plasma concentrations 24 h after intake correlated to plasma clearance (r(2)=0.84, P0.0000001). This correlation was confirmed in the comparison data set (r(2)=0.97, P0.0000001).A low dose of 125 mg tolbutamide can safely and accurately be used for CYP2C9 phenotyping. As a simple metric for CYP2C9 activity, we propose to determine tolbutamide in plasma 24 h after drug intake.

SummaryThe adenosine diphosphate (ADP) receptor P2Y12 blocking agent clopidogrel is clinically proven to be efficient in preventing thrombotic events. However, its therapeutic value is limited by an, as yet poorly explained, interindividual heterogeneity in platelet inhibition. To evaluate possible pharmacokinetic determinants of this response variability, we developed a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for quantification of unmodified inactive clopidogrel, its inactive carboxyl metabolite, and its active thiol metabolite in plasma. Analyte concentrations and platelet aggregation were assessed in ten healthy volunteers receiving an oral load of 600 mg clopidogrel. Subjects showed marked inter-individual differences in maximal platelet inhibition and in plasma pharmacokinetics. Univariate regression revealed linear correlations between maximal antiplatelet effect and peak plasma concentrations (cmax) of unchanged clopidogrel (r=0.76; p=0.01), of the carboxyl metabolite (r=0.70; p=0.03), and of the thiol metabolite (r=0.73; p=0.02), as well as linear correlations between cmax values of clopidogrel and its metabolites. This indicates that the response variability is predominantly caused by individual differences in clopidogrel absorption and that other factors, such as ADP receptor reactivity or differences in bioactivation of clopidogrel, do not play a major role.

Introduction Limited real world data are available regarding the effects of adalimumab (ADA) on UK patients with moderate to severe ulcerative colitis (UC). Methods INSPIRADA was a single-arm, multi-country, open-label study that evaluated the effect of ADA on patients with UC treated according to usual clinical practice. Adults with active moderate to severe UC who failed immunosuppressive therapies and experienced rectal bleeding within 7 days of baseline (BL) were enrolled. Prior use of anti-TNF was allowed. Clinical outcomes included Simple Clinical Colitis Activity Index (SCCAI) response (a decrease ≥2 points compared to BL) and remission (SCCAI ≤2). HRQoL (EQ-5D-5L and SIBDQ), treatment satisfaction with medication (TSQM), and work productivity and activity impairment (WPAI) were measured from BL to week 26. Direct medical costs (excluding ADA costs) were estimated using 2014 UK National Health Service reference costs. Indirect costs were based on the WPAI using average weekly earnings from the 2014 UK Annual Salary Survey of Hours and Earnings. Change (defined as 6 mo after start of ADA vs 6 mo before) in resource use and costs were calculated. Data for the intent-to-treat population in UK were analysed. Missing data were imputed using last observation carried forward. Results Data from 90 UK patients (58% male, mean age 39 yrs) were analysed. Mean SCCAI at BL was 8.2. At week 2, 74% achieved SCCAI response and 21% achieved SCCAI remission. At week 8, 73% achieved SCCAI response, 40% in remission and 49% had no blood in stool. At week 26, 66% achieved SCCAI response, 42% in remission and 51% had no blood in stool. Significant improvements, as early as within 2 weeks, in SIBDQ (19.5 points, p Conclusion Real world rates of response, remission and improvements in HRQoL with ADA for UK patients with moderate to severe UC were clinically meaningful. ADA improved work productivity, increased patient satisfaction with therapy and reduced health care associated costs for these patients in the UK. Disclosure of Interest P. Irving Grant/research support from: AbbVie; Falk; Ferring; Genentech/Roche; Hospira; Merck; Pharmacosmos; Shire; Takeda; Tillotts; Topivert; Vifor and Warner Chilcott, Conflict with: Advisor/invited lecturer for: AbbVie; Falk; Ferring; Genentech/Roche; Hospira; Merck; Pharmacosmos; Shire; Takeda; Tillotts; Topivert; Vifor and Warner Chilcott, F. Cummings Conflict with: Advisor/lectures for: Takeda, Abbvie, MSD, Biogen, Napp, Hospira, Janssen, S. Bloom Conflict with: Advisor/lectures for: Takeda, Tillotts, Abbvie, MSD, Pharmacosmos, Vifor, Johnson and Johnson, A. Lazar Shareholder of: AbbVie, Employee of: AbbVie, A. Robinson Shareholder of: AbbVie, Employee of: AbbVie, B. Pappalardo Shareholder of: AbbVie, Employee of: AbbVie, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, M. Skup Shareholder of: AbbVie, Employee of: AbbVie, N. Chen Shareholder of: AbbVie, Employee of: AbbVie, T. Finney-Hayward Shareholder of: AbbVie, Employee of: AbbVie, S. Wang Shareholder of: AbbVie, Employee of: AbbVie, R. Thakkar Shareholder of: AbbVie, Employee of: AbbVie, S. Travis Grant/research support from: AbbVie; Asahi; Boehringer Ingelheim; BMS; Cosmo; Elan; Ferring; FPRT Bio; Genentech/Roche; Genzyme; Glenmark; GW Pharmaceuticals; Lilly; Merck; Novartis; Novo Nordisk; Ocera; Pfizer; Shire; Santarus; SigmoidPharma; Synthon; Takeda; Tillotts; Topivert; Trino Therapeutics with Wellcome Trust; UCB Pharma; Vertex; VHsquared; Vifor; Warner Chilcott and Zeria, Conflict with: Advisor or paid instructor for: AbbVie; Asahi; Boehringer Ingelheim; BMS; Cosmo; Elan; Ferring; FPRT Bio; Genentech/Roche; Genzyme; Glenmark; GW Pharmaceuticals; Lilly; Merck; Novartis; Novo Nordisk; Ocera; Pfizer; Shire; Santarus; SigmoidPharma; Synthon; Takeda; Tillotts; Topivert; Trino Therapeutics with Wellcome Trust; UCB Pharma; Vertex; VHsquared; Vifor; Warner Chilcott and Zeria. All advisory boards were suspended Q1 2012–14 while President of ECCO

The extraneuronal monoamine transporter plays an important role in the inactivation of monoamine transmitters. A basal extraneuronal tissue expression of this transporter has been reported, but it is also expressed in CNS glia. As little is known about the expression pattern and the function of the extraneuronal monoamine transporter in the brain, we performed a detailed investigation. Firstly, a northern blot analysis of different rat organs revealed that the transporter is strongly expressed in placenta, lung and heart and less prominently in the whole brain, brain stem, intestine, testis, epididymis, stomach, kidney and skeletal muscle. It was not expressed in cerebellum, liver and embryo. Using an in situ hybridization to the rat brain, we detected a marked and highly confined expression of the extraneuronal monoamine transporter in the area postrema, but in no other brain areas. These findings were confirmed by polyclonal antibodies against rat extraneuronal monoamine transporter showing an intensive signal in the area postrema, although a few cells in the cerebellum and the brain stem also showed a signal. Additionally, a partly overlapping expression pattern of the monoamine oxidase-B was detected. Summarizing, we firstly describe a marked and highly confined expression of the extraneuronal monoamine transporter in the rat area postrema by in situ hybridisation which may play a role in physiological functions of this circumventricular organ such as emesis, food intake and the regulation of cardiovascular functions.

Plant phenols may exert protective effects by scavenging superoxide, which is implicated in tissue damage and accelerated inactivation of vasorelaxing nitric oxide. Preventing the interaction of superoxide with tissue biomolecules depends not only on the extent of superoxide scavenging but also on scavenging velocity. However, information on superoxide scavenging kinetics of plant phenols is scarce. We describe an improved lucigenin-based chemiluminescence assay for kinetic analysis. The use of potassium superoxide (KO2) as a nonenzymatic superoxide source allowed simple and reliable determination of the second-order reaction rate constants between superoxide and plant antioxidants at physiologically relevant conditions, avoiding unspecific effects of other reactive oxygen species or superoxide-generating enzymes. We calculated the rate constants for phenols of different structures, ranging from 2.9 × 103 mol-1 l s-1 for morin to 2.9 × 107 mol-1 l s-1 for proanthocyanidins. Compounds with pyrogallol or catechol moieties were revealed as the most rapid superoxide scavengers, and the gallate moiety was found to be the minimal essential structure for maximal reaction rate constants with superoxide.

OBJECTIVES: The safety and efficacy of adalimumab for patients with moderately to severely active ulcerative colitis (UC) has been reported up to week 52 from the placebo-controlled trials ULTRA (Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab) 1 and 2. Up to 4 years of data for adalimumab-treated patients from ULTRA 1, 2, and the open-label extension ULTRA 3 are presented. METHODS: Remission per partial Mayo score, remission per Inflammatory Bowel Disease Questionnaire (IBDQ) score, and mucosal healing rates were assessed in adalimumab-randomized patients from ULTRA 1 and 2 up to week 208. Corticosteroid-free remission was assessed in adalimumab-randomized patients who used corticosteroids at lead-in study baseline. Maintenance of remission per partial Mayo score and mucosal healing was assessed in patients who entered ULTRA 3 in remission per full Mayo score and with mucosal healing, respectively. As observed, last observation carried forward (LOCF) and nonresponder imputation (NRI) were used to report efficacy. Adverse events were reported for any adalimumab-treated patient. RESULTS: A total of 600/1,094 patients enrolled in ULTRA 1 or 2 were randomized to receive adalimumab and included in the intent-to-treat analyses of the studies. Of these, 199 patients remained on adalimumab after 4 years of follow-up. Rates of remission per partial Mayo score, remission per IBDQ score, mucosal healing, and corticosteroid discontinuation at week 208 were 24.7%, 26.3%, 27.7% (NRI), and 59.2% (observed), respectively. Of the patients who were followed up in ULTRA 3 (588/1,094), a total of 360 patients remained on adalimumab 3 years later. Remission per partial Mayo score and mucosal healing after ULTRA 1 or 2 to year 3 of ULTRA 3 were maintained by 63.6% and 59.9% of patients, respectively (NRI). Adverse event rates were stable over time. CONCLUSIONS: Remission, mucosal healing, and improved quality of life were maintained in patients with moderately to severely active UC with long-term adalimumab therapy, for up to 4 years. No new safety signals were reported.

SummaryBackground Patients with moderately to severely active ulcerative colitis occasionally do not respond to or lose initial response to maintenance dosing of anti-TNF therapy. Aim To report the efficacy of escalation from every other week (EOW) to weekly adalimumab dosing in patients from the clinical trial ULTRA 2 (NCT00408629), by week 8 response (i.e. response after adalimumab induction therapy). Methods Week 52 remission, response, and mucosal healing rates were assessed in ULTRA 2 adalimumab-randomised patients who escalated to weekly dosing. Patients were stratified by week 8 response per partial Mayo score. Kaplan–Meier and logistic regression analyses estimated time to weekly dosing and defined predictors of escalation to weekly dosing, respectively. Adverse events were reported for patients receiving open-label adalimumab. Results The rate of escalation to weekly dosing was 16.3% (20/123) for week 8 responders and 38.4% (48/125) for week 8 nonresponders. Week 52 remission, response and mucosal healing rates with weekly dosing were 20%, 45%, and 45% for week 8 responders and 2.1%, 25% and 29.2% for nonresponders, respectively (NRI). The median time to weekly dosing was 288 days for week 8 nonresponders and not estimable for responders. Prior anti-TNF use was a significant predictor of escalation to weekly dosing. Treatment-emergent adverse event rates were similar for patients receiving open-label EOW or weekly adalimumab. Conclusions Escalation to weekly adalimumab dosing demonstrated clinical benefits for patients who lost response to therapy and may be beneficial for patients not initially responding to induction therapy. No new safety risks were identified with weekly dosing.

The results of an open-label follow-up until week 52 of patients with moderately to severely active ulcerative colitis who participated in a double-blind placebo-controlled adalimumab induction trial (ULTRA 1, NCT00385736) are reported.The study included adult anti-tumor necrosis factor-naive patients who completed double-blind adalimumab induction under an amended protocol (intent-to-treat [ITT]-A3 population) or any version of the protocol (ITT-E). Patients randomized to placebo received adalimumab beginning at week 8; patients randomized to adalimumab continued every other week dosing. Weekly dosing was allowed beginning at week 14 (original protocol) or week 12 (amended protocol). Clinical remission (Mayo score ≤2, no subscore1), clinical response (decrease in Mayo score ≥3 points and ≥30% from baseline, plus decrease in rectal bleeding subscore ≥1 or absolute rectal bleeding subscore ≤1), mucosal healing (endoscopy subscore ≤1), escalation to weekly dosing, and reduction in corticosteroid use were assessed at week 52 in the pooled ITT-A3 and pooled ITT-E populations, using modified nonresponder imputation.Rates of clinical remission, clinical response, and mucosal healing at week 52 for the ITT-A3 population (N = 390) were 29.5%, 53.6%, and 46.7%, respectively; 38.8% of week 8 responders achieved clinical remission at week 52. Of patients using baseline corticosteroids (N = 234), 56.0% were corticosteroid-free at week 52 (26.1% in clinical remission). Results of the ITT-E population were similar. No new safety issues were identified.In this open-label study, adalimumab was effective for maintaining clinical remission in anti-tumor necrosis factor-naive patients with moderately to severely active ulcerative colitis who did not adequately respond to conventional therapy.

The IMAgINE 1 study (NCT00409682) evaluated the safety and efficacy of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients with moderate to severe Crohn's disease (CD).We studied 192 patients with Pediatric Crohn's Disease Activity Index (PCDAI) scores30 for whom conventional treatment was unsuccessful. Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight ≥40 kg or40 kg). At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as decrease in PCDAI ≥15 points from baseline; 155/188 [82.4%]) and prior exposure to infliximab (82/188 [43.6%]). Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for body weight ≥40 kg or40 kg; n = 93) or low doses (20 mg or 10 mg for body weight ≥40 kg or40 kg; n = 95) every other week for 48 weeks. Clinical remission (PCDAI ≤10) at week 26 (the primary end point) was compared between groups using the Cochran-Mantel-Haenszel test, adjusting for strata, with nonresponder imputation. Adverse events were monitored to evaluate safety.A total of 152 of 188 patients (80.9%) completed all 26 weeks of the study. At week 26, 63 patients (33.5%) were in clinical remission, with no significant difference between high- and low-dose groups (36/93 [38.7%] vs 27/95 [28.4%]; P = .075). No new safety signals were detected.Adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to that of adult patients with CD. More children who received high compared with low dose were in remission at week 26, but the difference between dose groups was not statistically significant.

Objective The aim of this study was to assess the efficacy and safety of adalimumab (ADA), a recombinant human monoclonal antibody against tumour necrosis factor a (TNF), for the induction of clinical remission in anti-TNF nao¨ve patients with moderately to severely active ulcerative colitis. Methods This 8-week, multicentre, randomised, doubleblind, placebo-controlled study (NCT00385736), conducted at 94 centres in North America and Europe, enrolled ambulatory adult patients with Mayo score of $6 points and endoscopic subscore of $2 points despite treatment with corticosteroids and/or immunosuppressants. Under the original study protocol, 186 patients were randomised (1:1) to subcutaneous treatment with ADA160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6) or placebo. Subsequently, at the request of European regulatory authorities, the protocol was amended to include a second induction group (ADA80/40: 80 mg at week 0, 40 mg at weeks 2, 4 and 6). The primary efficacy endpoint was clinical remission (Mayo score #2 with no individual subscore >1) at week 8, assessed in 390 patients randomised (1:1:1) to ADA160/80, ADA80/40, or placebo. Safety was assessed in all enrolled patients. Patients, study site personnel, investigators, and the sponsor were blinded to treatment assignment. Results At week 8, 18.5% of patients in the ADA160/80 group (p¼0.031 vs placebo) and 10.0% in the ADA80/40 group (p¼0.833 vs placebo) were in remission, compared with 9.2% in the placebo group. Serious adverse events occurred in 7.6%, 3.8% and 4.0% of patients in the placebo, ADA80/40, and ADA160/80 groups, respectively. There were two malignancies in the placebo group, none in the ADA groups. There were no cases of tuberculosis and no deaths. Conclusions ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants. Clinical trial NCT00385736.

s of the 3rd International Symposium on Pediatric Inflammatory Bowel Disease S421 by body weight ( 40kg, 160/80mg

68% had inflammatory (B1) disease behavior; 30% had prior resections. Over 7 years, 117 pts completed, while 478 discontinued (36% due to AEs; 28% due to pt decision; 17% due to no improvement/disease deterioration). Discontinuation rates were 29.2%, 13.6%, 16.1%, 7.9%, 5.0%, 4.5% and 3.9% during years 1 7, respectively. Over 71% of pts were exposed to CZP for >1 year; the average number of CZP injections was 41. No new safety signals were identified during this study. The most common AE was CD exacerbation (30%); most common OI was herpes simplex (3.4%). The observed annual remission rates ranged from 68% 76% (Year 1 to 7, table). The remission rates analyzed by LOCF and NRI methods were 58% and 45% at year 1, 56% and 26% at year 3 and 55% and 13% at year 7, respectively. FC levels had no trends toward change; CRP levels were relatively stable. The geometric mean CZP plasma concentrations ranged from 6 10 ug/mL up to year 6; CZP concentrations were typically lower in pts who were anti-CZP antibody positive vs. negative throughout the study (e.g. 3μg/ml vs. 9μg/ml at Wk 54, 3μg/ml vs. 10μg/ml at Wk 210, respectively). Conclusions: The P3 study demonstrates that the long-term safety of CZP is consistent with short-term studies.[1, 2] Additionally, the observed rates of clinical remission were sustainable for 7 years. PRECiSE3 Remission Rates Over 7 Years, observed cases