Factors that influence infliximab biosimilar trough levels in the pediatric inflammatory bowel disease population.

BACKGROUND: The pharmacokinetics and pharmacodynamics of biosimilar infliximab (IFX-BioS) in pediatric inflammatory bowel disease (IBD) are poorly investigated. The aim of this study was to investigate factors predicting IFX-BioS trough levels (TLs). RESEARCH DESIGN AND METHODS: IBD children with an indication to start IFX-BioS were included in this prospective observational study (January 2021-June 2022). TLs were measured at the 4th and 6th infusions and correlated with several covariates. RESULTS: A total of 110 TLs in 55 children were included. The multivariate linear regression model at the 4th infusion found a positive correlation between TLs and age at diagnosis (B:1.950, 95% CI: [0.019, 3.882], p = 0.048) and IFX-BioS dose/kg (B:1.962, 95% CI: [0.238, 3.687], p = 0.029), and a negative correlation with clinical scores (B:-0.401, 95% CI: [-0.738, -0.064], p = 0.023). At the 6th infusion, female gender (B:6.887, 95% CI: [0.861, 12.913], p = 0.029), hemoglobin (B:1.853, 95% CI: [0.501, 3.204], p = 0.011), and IFX-BioS dose/kg (B:1.792, 95% CI: [0.979, 2.605], p < 0.001) were found to be positively correlated to TLs. No association between combined clinical and biochemical remission and TLs was found. CONCLUSIONS: This study discovered some predictors for IFX-BioS TLs in IBD children. Knowledge of predictive factors could help physicians choose the best dosing regimen.

Efficacy, safety, and pharmacokinetics of teduglutide in adult Japanese patients with short bowel syndrome and intestinal failure: two phase III studies with an extension.

PURPOSE: The short- and long-term efficacy, safety, and pharmacokinetics of teduglutide were analyzed in adult Japanese patients with short bowel syndrome and intestinal failure (SBS-IF). METHODS: Patients received teduglutide 0.05 mg/kg/day in clinical trials (TED-C14-004, SHP633-306, and extension SHP633-307). Data were analyzed at 24 weeks and an interim data cut-off of 4.5 years. RESULTS: The parenteral support (PS) volume decreased by ≥ 20% for 9/18 patients at 24 weeks and in all 11 patients by data cut-off in SHP633-307. The mean (standard deviation) PS volume decreased from baseline at 24 weeks in TED-C14-004 (-30.1 ± 25.9%) and SHP633-306 (-25.6 ± 25.5%), and at data cut-off in SHP633-307 (-57.08 ± 28.49%). Teduglutide was absorbed quickly. The adverse events were consistent with the underlying disease and known adverse drug reactions. Anti-teduglutide antibody titers declined with long-term treatment. CONCLUSIONS: In Japanese adults with SBS-IF, teduglutide treatment was associated with clinically meaningful reductions in PS requirements, similar to findings in prior international studies. No new safety concerns specific to the Japanese SBS-IF patient population were identified with short- or long-term teduglutide treatment. Anti-teduglutide antibody titers disappeared in most Japanese adults with long-term treatment. These results constitute the longest evaluation of teduglutide treatment within clinical trials reported to date.

Early Infliximab Clearance Predicts Remission in Children with Crohn's Disease.

BACKGROUND AND AIMS: Children with Crohn's disease have lower response rates to infliximab, lower infliximab levels, and higher infliximab clearance on weight-based dosing than adults. We hypothesize infliximab clearance is a predictive of later outcomes on infliximab in children with Crohn's disease. METHODS: In this single-center retrospective study, data were collected from charts on diagnosis, anthropometry, routine labs, infliximab therapeutic drug monitoring, infliximab dosing, disease activity, and other treatments. With these data we generated a population pharmacokinetic model using non-linear mixed effects modeling and calculated infliximab clearance for each patient over time. Patients were classified as in remission, responder-only or non-responder at 5, 10 and 16 months. Regression and ROC analyses were used to assess for early predictors of remission and response to infliximab. RESULTS: Eighty-five subjects were included, with a median follow-up of 22.3 months (IQR 10.1-36.8). Our pharmacokinetic model showed infliximab clearance was positively associated with CRP and weight, while negatively associated with albumin. In regression analyses, early infliximab clearance was the only significant, consistent predictor of remission. A 0.1 L/day increase in infliximab clearance predicted remission with an OR between 0.179 and 0.426. Differences in dosing did not account for differences in outcome. Infliximab clearance alone had moderate predictive accuracy of remission, with an AUC between 0.682 and 0.738. CONCLUSIONS: Early infliximab clearance is strongly associated with remission in children with Crohn's disease. It may be useful as a marker of response in proactive therapeutic drug monitoring to guide early dose optimization and/or changes in treatment for betterment of long-term outcomes.

Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn's Disease: Results from the Phase 2 HUBBLE Study.

BACKGROUND AND AIMS: To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD. METHODS: Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed. RESULTS: Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies. CONCLUSIONS: Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified.

Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases.

BACKGROUND: The loss of response to infliximab is a challenge for clinicians in the management of inflammatory bowel disease (IBD). Mounting evidence suggests that therapeutic drug monitoring at induction may predict remission during maintenance. The aim of the study was to improve predictive models of remission by exploring new peak and intermediate infliximab measurements during induction. METHODS: This was a prospective multicenter study evaluating the pharmacokinetics of infliximab during induction in a pioneer cohort of 63 patients with IBD. Pharmacokinetics data including peak, intermediate, and trough levels were combined with clinical and biological parameters and were subsequently fed into tailored logistic regression and tree-based techniques to predict remission at week 30. RESULTS: Infliximab peak levels at week 2, intermediate levels at week 3, and trough levels at week 6 were correlated with remission at week 30. Predictive models exhibited an increased accuracy over the successive timepoints of the induction with key inputs such as albumin, C-reactive protein, eosinophils, neutrophils, lymphocytes, intermediate level at week 3, trough level at week 6, and age at diagnosis. Our predictive model of remission at week 30 was obtained with an area under the receiver operating characteristic curve of 0.9 ±â€…0.12, a sensitivity of 89%, and a specificity of 75%. CONCLUSIONS: This study showed the clinical relevance of measuring new infliximab levels to predict remission in patients with IBD. These findings lay the foundation for a personalized medicine in which biotherapies could be monitored at an early stage, thereby improving patients' clinical management.

Predictors of Immunogenicity to Infliximab among Patients with Inflammatory Bowel Disease: Does Ethnicity Matter?

BACKGROUND: Up to 60% of inflammatory bowel disease (IBD) patients treated with infliximab develop antibodies to infliximab (ATI), which are associated with low drug levels and loss of response (LOR). Hence, mapping out predictors of immunogenicity toward infliximab is essential for tailoring patient-specific therapy. Jewish Sephardi ethnicity, in addition to monotherapy, has been previously identified as a potential risk factor for ATI formation and infliximab failure. OBJECTIVES: To explore the association between Jewish sub-group ethnicity among patients with IBD and the risk of infliximab immunogenicity and therapy failure. To confirm findings of a previous cohort that addressed the same question. METHODS: This retrospective cohort study included all infliximab-treated patients of Jewish ethnicity with regular prospective measurements of infliximab trough levels and ATI. Drug and ATI levels were prospectively measured, clinical data was retrieved from medical charts. RESULTS: The study comprised 109 Jewish patients (54 Ashkenazi, 55 Sephardi) treated with infliximab. There was no statistically significant difference in proportion of ATI between Sephardi and Ashkenazi patients with IBD (32% Ashkenazi and 33% Sephardi patients developed ATI, odds ratio [OR] 0.944, P = 0.9). Of all variables explored, monotherapy and older age were the only factors associated with ATI formation (OR 0.336, 95% confidence interval 0.145-0.778, P = 0.01, median 34 vs. 28, interquartile range 28-48, 23-35 years, P = 0.02, respectively). CONCLUSIONS: Contrary to previous findings, Sephardi Jewish ethnicity was not identified as a risk factor for ATI formation compared with Ashkenazi Jewish ethnicity. Other risk factors remained unchanged.

Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers.

Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [14C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs. 0.8 hours). The short intravenous half-life was consistent with high systemic clearance (61.9 l/h) and low volume of distribution (16.3 l). In vitro studies predicted rapid hepatic clearance via cytochrome P450 3A4 metabolism, which predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ∼80% elimination via biliary/fecal excretion (>90%-97% as unchanged parent) and ∼20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily because of a very low fraction absorbed (0.167%; fraction escaping first-pass gut metabolism (fg) ∼100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ∼20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (<0.04% of dose). Linerixibat unequivocally exhibited minimal gastrointestinal absorption and oral systemic exposure. Linerixibat represents a unique example of high CYP3A4 clearance in vitro but nearly complete excretion as unchanged parent drug via the biliary/fecal route. SIGNIFICANCE STATEMENT: This study conclusively established minimal absorption and systemic exposure to orally administered linerixibat in humans. The small amount of linerixibat absorbed was eliminated efficiently as unchanged parent drug via the biliary/fecal route. The hepatic clearance mechanism was mispredicted to be mediated via cytochrome P450 3A4 metabolism in vitro rather than biliary excretion of unchanged linerixibat in vivo.

PTG-100, an Oral α4ß7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis.

BACKGROUND & AIMS: Oral therapies targeting the integrin α4ß7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4ß7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). METHODS: In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. RESULTS: PTG-100 potently and selectively blocks α4ß7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. CONCLUSIONS: PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4ß7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75).

Population pharmacokinetics and exposure-response analyses of teduglutide in adult and pediatric patients with short bowel syndrome.

Teduglutide is a recombinant analog of human glucagon-like peptide-2 that regulates the functional and structural integrity of the cells lining the gastrointestinal tract. Teduglutide is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support (PS). Population pharmacokinetic (PK) and exposure-response analyses were performed to support teduglutide dosing in patients with SBS. The analysis included 219 patients with SBS (aged <1 year, 5 patients; 1-11 years, 86 patients; 12-17 years, 8 patients; 18-79 years, 120 patients), and 259 non-SBS subjects (including healthy volunteers and subjects with renal or liver impairment). A one-compartment model with first-order absorption and linear elimination adequately characterized the PKs of teduglutide. In patients with SBS, the apparent clearance (CL/F), volume of distribution (V/F), and elimination half-life of teduglutide were 16.0 L/h, 33.9 L, and 1.47 h, respectively. CL/F depended on body weight and renal function, and V/F depended on body weight and age. Maximum concentration (Cmax ) of teduglutide was similar in adult and pediatric patients, and in Japanese and non-Japanese patients. A time- and exposure-response model dependent on the Cmax of teduglutide adequately characterized the reduction in PS over more than 2 years of treatment. Daily dosing of 0.05 mg/kg teduglutide resulted in a maximum reduction in PS of 5.76 L/week. Higher Cmax values were associated with a more important reduction in PS over time. Adult and pediatric patients with SBS presented similar PKs and response to teduglutide.

Formulation development and in-vitro evaluation of gastroretentive drug delivery system of loxoprofen sodium: A natural excipients based approach.

The limitations of conventional type delivery systems to retain drug (s) in the stomach has resulted in the development of novel gastroretentive drug delivery system. We developed single-layer effervescent floating tablets of loxoprofen sodium for prolong delivery in the stomach using natural polymers xanthan gum, guar gum and semisynthetic polymer HPMCK4M. All the formulations (F1-F9) were developed by varying concentrations of xanthan gum and HPMCK4M while guar gum concentration was kept constant. Two gas generating agent (s) incorporated were sodium bicarbonate and citric acid. All compendial pre and post-compression tests results were in the acceptable limits. FTIR analysis confirmed drug-polymer compatibility. The in-vitro drug release in simulated conditions i.e., 0.1 N HCl for 12 h revealed orderly increase in total floating time, i.e., less than 6 h for F1 over 12 h for F9. Formulations F1 to F4 were not capable to retard drug release up to 12 h, whereas F5-F7 for 12 h, while F8 and F9 for more than 12 h. Data fitting in various kinetic models showed that drug release best fit in first order kinetic model and F9 in zero order. Based on results data, F7 was the best among all.

Long-Term Safety and Efficacy of Risankizumab Treatment in Patients with Crohn's Disease: Results from the Phase 2 Open-Label Extension Study.

BACKGROUND AND AIMS: Risankizumab, an interleukin-23 antibody, demonstrated efficacy and acceptable safety in a phase 2 study of patients with moderate-to-severe refractory Crohn's disease. This open-label extension investigated the long-term safety, pharmacokinetics, immunogenicity and efficacy of risankizumab in responders to risankizumab in the parent phase 2 study. METHODS: Enrolled patients had achieved clinical response [decrease in Crohn's Disease Activity Index from baseline ≥100] without clinical remission [Crohn's Disease Activity Index <150] at Week 26, or clinical response and/or remission at Week 52 in the parent phase 2 study and received open-label subcutaneous risankizumab 180 mg every 8 weeks. RESULTS: Sixty-five patients were enrolled, including four who had lost response in the parent study and were first reinduced with risankizumab 600 mg every 4 weeks [three infusions]. Patients received risankizumab for a median of 33 months [total: 167.0 patient-years]. The rate of serious adverse events was 24.6 events/100 patient-years; the majority were gastrointestinal in nature. Rates of serious infections, opportunistic infections and fungal infections were 4.2, 1.8, and 6.6 events/100 patient-years, respectively. No deaths, malignancies, adjudicated major adverse cardiovascular events, latent/active tuberculosis or herpes zoster were reported. Treatment-emergent anti-drug antibodies developed in eight patients [12.3%]; none were neutralizing. Efficacy outcomes were maintained during the study, including the proportions of patients [observed analysis] with clinical remission [>71%] and endoscopic remission [>42%]. CONCLUSIONS: Long-term maintenance treatment with subcutaneous risankizumab 180 mg every 8 weeks was well tolerated by patients with Crohn's disease, with no new safety signals. Clinical trial registration number: NCT02513459.

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide.

PURPOSE: Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. METHODS: As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. RESULTS: LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. CONCLUSION: The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Single- and Multiple-Dose Pharmacokinetics and Pharmacodynamics of PN-943, a Gastrointestinal-Restricted Oral Peptide Antagonist of α4ß7, in Healthy Volunteers.

PN-943 is an orally stable, gastrointestinal-restricted peptide that binds specifically to α4ß7 integrin on leukocytes, blocking leukocyte trafficking to and activation in the gut, inhibiting colon inflammation and reducing signs and symptoms of active ulcerative colitis. Two pharmacokinetic/pharmacodynamic studies were conducted in healthy volunteers. Study 1 was a first-in-human study with 40 male subjects receiving PN-943, 100 to 1400 mg or placebo, as single doses and 57 male subjects receiving PN-943, 100 to 1000 mg or placebo, as multiple doses. Study 2 was a randomized, crossover study comparing multiple doses of 450-mg PN-943 twice daily as a liquid solution and as an immediate-release tablet in 10 subjects. No subjects discontinued due to treatment-emergent adverse events. Consistent with the gastrointestinal-restricted nature of the peptide, systemic exposure was minimal; there was an approximate dose-proportional increase in area under the plasma concentration-time curve. There was minimal accumulation with once-daily dosing and an absence of time-dependent changes in pharmacokinetics. Administration of PN-943 after a high-fat meal reduced peak plasma concentration and area under the plasma concentration-time curve. There was minimal (<0.1%) urinary excretion of intact drug, and there was a dose-related increase in fecal excretion of intact PN-943. Dose-dependent increases in blood receptor occupancy and reduction in blood receptor expression were observed, supporting target engagement. Twice-daily dosing resulted in sustained receptor occupancy with low plasma fluctuations (143%). PN-943 was generally well tolerated following single and multiple oral doses with low systemic exposure. Twice-daily dosing resulted in sustained pharmacokinetics and pharmacodynamics, supporting further investigation in efficacy studies.

Comparison of three immunoassays for infliximab trough level monitoring in paediatric inflammatory bowel diseases.

Many clinical studies in paediatric inflammatory bowel diseases (IBD) use infliximab trough level (IFX-TL) and detection of antibody against infliximab (ATI). Hence, comparison of commercially available assays is needed in paediatric samples to assess their reliability and their comparability. We measured IFX-TL and ATI-TL in sera samples of 53 IBD children using three ELISA kits: Lisa-Tracker® Duo Infliximab (Theradiag®), Ridascreen® IFX monitoring (R-Biopharm®) and Promonitor® IFX (Grifols®). Regarding IFX-TL, median values were comparable (p > 0.05), a good statistical correlation has been observed (0.73 ≤ R2 ≤ 0.85) between tested assays and the Bland-Altman analysis found an excellent agreement with a bias estimated between -0.56 and 0.12 and few values outside the 95% limits of agreement. However, qualitative comparison with therapeutic interval classifications showed some discrepancies (30.2%), mainly due to values near thresholds and more often than not with Theradiag® (22.6%). For ATI, because of non-standardized units, the qualitative comparison found a sensibly good agreement (98.1%). These data show a good agreement of IFX-TL and ATI measurement between three marketed ELISA assays with a small bias obtained. Variations in some results can lead to divergent therapeutic interval classifications and prompt us to be cautious in the interpretation of values near therapeutic thresholds.

Tissue Exposure does not Explain Non-Response in Ulcerative Colitis Patients with Adequate Serum Vedolizumab Concentrations.

BACKGROUND AND AIMS: Some patients with ulcerative colitis [UC] do not respond to vedolizumab treatment despite adequate drug exposure in serum. This study aimed to investigate vedolizumab in tissue and questioned whether insufficient tissue exposure could explain non-response in UC patients with adequate serum vedolizumab concentrations. METHODS: A paired serum sample and colonic mucosal biopsy was collected from 40 UC patients [20 endoscopic responders, 20 non-responders] at week 14 of vedolizumab treatment. Vedolizumab, soluble [s]-mucosal addressin cell adhesion molecule-1 [MAdCAM-1], s-vascular cell adhesion molecule-1 [VCAM-1] and s-intercellular adhesion molecule-1 [ICAM-1] were measured in serum and/or tissue. Endoscopic response was defined as Mayo endoscopic sub-score ≤1. RESULTS: A significant positive correlation was observed between vedolizumab serum and colonic tissue concentrations [ρ = 0.84, p < 0.0001], regardless of the macroscopic inflammatory state of the tissue. Vedolizumab tissue concentrations were lower in non-responders than in responders [0.07 vs 0.11 µg/mg, p = 0.04]. In the subgroup of patients with adequate vedolizumab serum concentrations [>14.6 µg/mL], tissue vedolizumab was not significantly different between responders and non-responders [0.15 vs 0.13 µg/mg; p = 0.92]. Serum sMAdCAM-1 concentrations, but not serum sICAM-1 or sVCAM-1 concentrations, were significantly higher in responders than in non-responders with adequate vedolizumab serum concentrations [1.04 vs 0.83 ng/mL, p = 0.03]. CONCLUSIONS: Vedolizumab concentrations in colonic mucosal tissue of UC patients reflect the concentration in serum regardless of the macroscopic inflammatory state of the tissue. Our data show that insufficient tissue exposure does not explain non-response in UC patients with adequate serum vedolizumab concentrations.

Association Between Vedolizumab Levels, Anti-vedolizumab Antibodies, and Endoscopic Healing Index in a Large Population of Patients with Inflammatory Bowel Diseases.

BACKGROUND: The aim of this study was to assess the relationship between serum vedolizumab (VDZ) concentrations and antibodies to VDZ (ATV) in a large cohort of patients with inflammatory bowel diseases. Furthermore, we evaluated the association between serum VDZ concentrations and a novel serum-based biomarker panel designated as the endoscopic healing index (EHI), developed and validated for identifying mucosal inflammation in patients with Crohn's disease (CD). METHODS: Retrospective study where results from patient samples submitted to a commercial clinical laboratory were included. Serum VDZ and ATV levels were analyzed using a drug-tolerant assay. In CD patients for whom both VDZ and EHI were available, VDZ concentrations were correlated with EHI. serum VDZ threshold analysis was performed using ROC curves, and the serum VDZ concentrations that best differentiated EHI < 20 (previously associated with endoscopic remission) were chosen. RESULTS: A total of 9356 patients were included in the VDZ/ATV analysis. Detectable ATV was observed in 2.9% patients with significantly lower serum VDZ concentrations when compared to those with undetectable ATV [3.9 µg/mL (0-9.0) vs. 11.3 µg/mL (5.9-20.6), p < 0.0001]. Of the patients with serum VDZ result, 287 patients had a concomitant EHI test. An inverse correlation was observed between VDZ concentration and EHI (rho = - 0.20, p < 0.001). A serum VDZ concentration ≥ 15.7 µg/ml was best correlated wi th an EHI < 20 [AUROC: 0.67 (95% CI 0.57-0.77)]. CONCLUSIONS: Incidence of ATVs was low, but significantly associated with lower VDZ levels. A serum VDZ concentration threshold of ≥ 15.7 µg/ml was associated with endoscopic remission as defined by an EHI < 20.

Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease.

BACKGROUND: Infliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics. METHODS: The study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed-effects population pharmacokinetic modeling. RESULTS: Dose-normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10-21) compared to prepregnancy (7, 2-12; p = 0.003), the first trimester (9, 1-12; p = 0.04), or postpregnancy (6, interquartile range 3-11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7-36; p > 0.05). A one-compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti-infliximab antibodies, and not by pregnancy-imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre- and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester. CONCLUSION: Infliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de-intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.

Infliximab Trough Levels Are Not Predictive of Relapse in Patients with IBD in Endoscopic Remission: A Multicenter Cohort Study.

BACKGROUND: Therapeutic drug monitoring (TDM) is important in optimizing use of biologics in inflammatory bowel diseases (IBD). However, the role of proactive TDM during remission remains uncertain. METHODS: This retrospective study included patients receiving infliximab (IFX) therapy at Massachusetts General Hospital or Erasmus University Medical Center. All eligible patients had completed induction phase of IFX and were in clinical and endoscopic remission. Our primary outcome was clinical relapse within 2 years after baseline. Multivariable regression models examined the association between infliximab trough levels during remission and relapse, need for IBD-related surgery or hospitalization. RESULTS: Our study cohort included 110 patients with IBD (72 CD, 38 UC) on IFX maintenance therapy. In total, 12 patients (10.9%) experienced relapse of disease over 2 years. The mean IFX trough level at baseline was 8.0 µg/mL (± 8.6) and did not differ between the institutions. 49.1% of patients had levels < 5 µg/mL and 2.7% had antibodies to infliximab at baseline. There was no difference in the mean IFX trough levels between patients who relapsed (7.5 µg/mL ± 3.7 µg/mL) over 24 months compared to those who did not (8.1 µg/mL ± 7.9 µg/mL, p = 0.815). On multivariable logistic regression analysis, IFX trough levels at baseline were not associated with relapse of disease over 24 months (OR 1.01, 95% CI 0.93-1.09, p = 0.856). CONCLUSION: This retrospective multicenter study provides evidence that IFX trough levels during quiescent disease do not predict relapse over 2 years, suggestive that proactive TDM in this setting is not warranted.

Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA). METHODS: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi, and bile ducts by positron emission tomography of the liver using the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. RESULTS: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. CONCLUSIONS: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. LAY SUMMARY: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.

Pharmacokinetics and Pharmacodynamics of Tegoprazan Coadministered With Amoxicillin and Clarithromycin in Healthy Subjects.

This clinical trial was conducted to evaluate the pharmacokinetics and pharmacodynamics of tegoprazan when coadministered with amoxicillin/clarithromycin in healthy subjects. Cohort 1 was an open-label, randomized multiple-dose study to evaluate the mutual interaction of tegoprazan and amoxicillin/clarithromycin on the disposition of 3 tested drugs including tegoprazan M1 metabolite and 14-hydroxyclarithromycin (14-OH-clarithromycin). Cohort 2 was an open-label, randomized, active-controlled, parallel multiple-dose study to compare the intragastric pH profile after multiple oral doses of 50 or 100 mg tegoprazan coadministered with amoxicillin/clarithromycin 1000/500 mg for 7 days and pantoprazole-based triple therapy as the comparator arm. The coadministration of tegoprazan with amoxicillin/clarithromycin increased Css,max (2.2-fold) and AUCτ (2.7-fold) of tegoprazan and M1 (2.1- and 2.2-fold for Css,max and AUCτ , respectively) compared with administration of tegoprazan alone. The Css,max and AUCτ of 14-OH-clarithromycin increased by 1.7- and 1.8-fold, respectively; the disposition of amoxicillin and clarithromycin were not significantly changed. On days 1 and 7 of treatment, tegoprazan-based therapies (both 50- and 100-mg therapies) maintained pH above 6 for more than 88% of the 24-hour period, which was significantly longer compared with pantoprazole-based therapy. Tegoprazan either alone or in combination with amoxicillin/clarithromycin was well tolerated in healthy subjects. In conclusion, the exposure of tegoprazan was increased after coadministration of amoxicillin/clarithromycin, which led to increase pharmacodynamic response measured by intragastric pH compared with tegoprazan alone. Therefore, tegoprazan-based triple therapy would be effective therapeutic regimen to manage intragastric pH in terms of gastric or duodenal ulcers healing, treatment of gastroesophageal reflux disease, and Helicobacter pylori eradication.