Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

BACKGROUND: Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. METHODS: The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. RESULTS: Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. CONCLUSIONS: Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model.

BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. OBJECTIVE: The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. METHODS: This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). RESULTS: Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066 L/h/46.4 kg, 0.0055 L/h/46.4 kg, 0.0081 L/h/46.4 kg, 0.0029 L/h/46.4 kg, 0.6750 L/46.4 kg, and 1.19 L/46.4 kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. CONCLUSIONS: A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

Performance of Eight Infliximab Population Pharmacokinetic Models in a Cohort of Dutch Children with Inflammatory Bowel Disease.

BACKGROUND AND OBJECTIVE: Efficacy of infliximab in children with inflammatory bowel disease can be enhanced when serum concentrations are measured and further dosing is adjusted to achieve and maintain a target concentration. Use of a population pharmacokinetic model may help to predict an individual's infliximab dose requirement. The aim of this study was to evaluate the predictive performance of available infliximab population pharmacokinetic models in an independent cohort of Dutch children with inflammatory bowel disease. METHODS: In this retrospective study, we used data of 70 children with inflammatory bowel disease (443 infliximab concentrations) to evaluate eight models that focused on infliximab pharmacokinetic models in individuals with inflammatory bowel disease, preferably aged ≤ 18 years. Predictive performance was evaluated with prior predictions (based solely on patient-specific covariates) and posterior predictions (based on covariates and infliximab trough concentrations). Model accuracy and precision were calculated with relative bias and relative root mean square error and we determined the classification accuracy at the trough concentration target of ≥ 5 mg/L. RESULTS: The population pharmacokinetic model by Fasanmade was identified to be most appropriate for the total dataset (relative bias before/after therapeutic drug monitoring: -20.7%/11.2% and relative root mean square error before/after therapeutic drug monitoring: 84.1%/51.6%), although differences between models were small and several were deemed suitable for clinical use. For the Fasanmade model, sensitivity and specificity for maximum posterior predictions for the next infliximab trough concentration to be ≥ 5 mg/L were respectively 83.5% and 80% with an area under the receiver operating characteristic curve of 0.870. CONCLUSIONS: In our paediatric cohort, various models provided acceptable predictive performance, with the Fasanmade model deemed most suitable for clinical use. Model-informed precision dosing can therefore be expected to help to maintain infliximab trough concentrations in the target range.

Combination Therapy With Guselkumab and Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Pharmacokinetics, Immunogenicity and Drug-Drug Interactions.

A proof-of-concept study with the combination of guselkumab and golimumab in patients with ulcerative colitis (UC) has shown that the combination therapy resulted in greater efficacy than the individual monotherapies. The current analysis evaluated the pharmacokinetics (PK) and immunogenicity of guselkumab and golimumab in both the combination therapy and individual monotherapies. Blood samples were collected to evaluate serum concentrations and immunogenicity of guselkumab and golimumab. Population PK (PopPK) models were developed to assess the effects of combination therapy and other potential covariates on the PK of guselkumab and golimumab. The guselkumab PK was comparable between monotherapy and combination therapy, whereas golimumab concentrations were slightly higher with combination therapy. The anti-guselkumab antibody incidence was low with both monotherapy and combination therapy, and guselkumab immunogenicity did not impact the clearance. Conversely, the anti-golimumab antibody incidence with combination therapy was lower than that for monotherapy. PopPK analysis suggested that the slightly higher golimumab concentrations with combination therapy were partially due to lower immunogenicity and thus lower clearance with combination therapy. C-reactive protein (CRP) was also a significant covariate on golimumab clearance. The greater improvement of inflammation with combination therapy, as shown by reductions in CRP, may have also contributed to the higher golimumab concentrations. Combination therapy slightly decreased the clearance of golimumab, but not guselkumab clearance, in patients with UC. Lower immunogenicity and greater improvement of inflammation with combination therapy were potential mechanisms for slightly increased golimumab concentrations with combination therapy as compared with golimumab monotherapy.

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.

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.

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.

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.

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.

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.

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.

Optimization of infliximab therapy in inflammatory bowel disease using a dashboard approach-an Indian experience.

PURPOSE: Infliximab (IFX) therapy in inflammatory bowel disease (IBD) is associated with loss of response in half the patients, due to complex pharmacokinetic and immunological factors. Dashboard's Bayesian algorithms use information from model and individual multivariate determinants of IFX concentration and can predict dose and dosing interval. AIM: To compare measured IFX concentrations in our laboratory with values predicted by iDose dashboard system and report its efficacy in managing patients not responding to conventional dosing schedule. METHOD: Clinical history, demographic details, and laboratory findings such as albumin and C-reactive protein (CRP) data of IBD patients (n = 30; median age 23 years (IQR: 14.25 - 33.5)) referred for IFX drug monitoring in our laboratory from November 2017 to November 2019 were entered in iDose software. The IFX concentration predicted by iDose based on this information was compared with that measured in our laboratory. In addition, a prospective dashboard-guided dosing was prescribed in 11 of these 30 patients not responding to conventional dosing and was followed to assess their clinical outcome. RESULT: IFX monitoring in our 30 patients had shown therapeutic concentration in 12, supratherapeutic in 2 and subtherapeutic concentration in 16 patients. The iDose predicted concentration showed concordance in 21 of these 30 patients. Of 11 patients managed with iDose-assisted prospective dosing, 8 achieved clinical remission, 2 showed partial response, and one developed antibodies. CONCLUSION: Retrospective data analysis showed concordance between laboratory measured and iDose-predicted IFX level in 70% of patients. iDose-assisted management achieved clinical remission and cost reduction.