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Crohn's disease (CD) is characterized by a remitting and relapsing course. Longstanding active CD may result in accumulating intestinal damage and disease-related complications. In contrast, mucosal healing is associated with significant improvement in the health-related quality of life, longer periods of disease remission and lower risk of disease progression, complications, hospitalizations, intestinal surgeries, as well as a lower risk of developing colorectal cancer. Mucosal healing, the new treatment endpoint in CD, made necessary the development of noninvasive, accurate, objective and reliable tools for the evaluation of CD activity. Ileocolonoscopy with biopsies remains the reference standard method for the evaluation of the colonic and terminal ileal mucosa. However, it is an invasive procedure with a low risk of complications, allowing the investigation of only a small part of the small bowel mucosa without being able to assess transmural inflammation. These disadvantages limit its role in the frequent follow up of CD patients. In this review, we present the currently available biomarkers and imaging modalities for the noninvasive assessment of CD activity.

The development of fibrostenotic intestinal disease occurs in approximately one-third of patients with Crohn’s disease and is associated with increased morbidity. Despite introducing new biologic agents, stricturing Crohn’s disease remains a significant clinical challenge. Medical treatment is considered the first-line treatment for inflammatory strictures, and anti-TNF agents appear to provide the most considerable benefit among the available medical treatments. However, medical therapy is ineffective on strictures with a mainly fibrotic component, and a high proportion of patients under anti-TNF will require surgery. In fibrotic strictures or cases refractory to medical treatment, an endoscopic or surgical approach should be considered depending on the location, length, and severity of the stricture. Both endoscopic balloon dilatation and endoscopic stricturoplasty are minimally invasive and safe, associated with a small risk of complications. On the other hand, the surgical approach is indicated in patients not suitable for endoscopic therapy. This review aimed to present and analyze the currently available medical, endoscopic, and surgical management of stricturing Crohn’s disease.

Two phase I studies assessed the drug–drug interaction potential of apalutamide as a substrate and perpetrator. Study A randomized 45 healthy men to single-dose apalutamide 240 mg alone or with strong inhibitors of cytochrome P450 (CYP)3A4 (itraconazole) or CYP2C8 (gemfibrozil). In study B, 23 patients with castration-resistant prostate cancer received probes for CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP2C8 (pioglitazone), and transporter substrates for P-glycoprotein (P-gp) (fexofenadine) and breast cancer resistance protein (BCRP)/organic anion transporting polypeptide (OATP) 1B1 (rosuvastatin) at baseline and after repeat once-daily administration of apalutamide 240 mg to steady state. Systemic exposure (area under the plasma concentration–time curve) to single-dose apalutamide increased 68% with gemfibrozil but was relatively unchanged with itraconazole (study A). Apalutamide reduced systemic exposure to midazolam ↓92%, omeprazole ↓85%, S-warfarin ↓46%, fexofenadine ↓30%, rosuvastatin ↓41%, and pioglitazone ↓18% (study B). After a single dose, apalutamide is predominantly metabolized by CYP2C8, and less by CYP3A4. Co-administration of apalutamide with CYP3A4, CYP2C19, CYP2C9, P-gp, BCRP or OATP1B1 substrates may cause loss of activity for these medications. Therefore, appropriate mitigation strategies are recommended.

Hepatitis E virus (HEV) is a significant health problem with approximately 20 million individuals infected annually. HEV infection has been associated with a wide spectrum of extrahepatic manifestations, including neurological, hematological and renal disorders. Guillain-Barré syndrome and neuralgic amyotrophy are the most frequent neurological manifestations. In addition, HEV infection has been observed with other neurological diseases, such as encephalitis, myelitis and Bell’s palsy. Hematologic manifestations include anemia due to glucose-6-phospate dehydrogonase deficiency, autoimmune hemolytic anemia and severe thrombocytopenia. Membranoproliferative glomerulonephritis and relapse IgA nephropathy with or without coexisting cryoglobulinemia appear to be the most common renal injuries related with HEV infection. Also, HEV infection has been associated with acute pancreatitis and other immune-mediated manifestations, such as arthritis and myocarditis. However, the pathophysiologic mechanisms of HEV-related extrahepatic manifestations are still largely unclear.

Primary sclerosing cholangitis (PSC) is a chronic and progressive disease of the biliary tract. PSC is strongly associated with inflammatory bowel disease (IBD), mainly with ulcerative colitis, and most PSC patients have underlying IBD. The pathophysiological interactions between IBD and PSC are unclear, although it seems that the patients with IBD and PSC have a distinct phenotype. IBD with coexisting PSC is more extensive and is characterized by milder activity compared to IBD alone. The coexistence of PSC increases the risk for colorectal cancer in IBD patients and lifelong annual surveillance colonoscopy is recommended. Also, liver transplantation (LT) for PSC may affect the course of IBD. In addition, the management of IBD after LT includes many specific problems. On the other hand, the effect of IBD on the natural history of PSC appears to be milder. However, IBD may increase the risk of postsurgical complications after LT and is a risk factor for recurrent PSC after LT. Overall, the coexistence of IBD with PSC changes the management, natural history and prognosis of both diseases.

Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved for patients with advanced EGFR exon 20 insertion non-small cell lung cancer after progression on platinum-based chemotherapy. First-dose intravenous (IV) delivery leads to infusion-related reactions (IRR) among 66% of patients, resulting in dose interruptions and slower infusion restart rates (infusion duration ranges 2-4 hours) and necessitates splitting of the dose over 2 days (Park Ann Oncol 32[suppl_5]:S981). Subcutaneous (SC) administration of amivantamab, which could simplify and accelerate administration, is being investigated in an ongoing phase 1 study (PALOMA; NCT04606381). Preliminary safety (including IRR) and pharmacokinetics (PK) of SC formulations of amivantamab ± recombinant human hyaluronidase (rHuPH20) for enhanced absorption were evaluated. Methods: PALOMA is an ongoing phase 1 dose escalation study of amivantamab SC in patients with advanced solid tumors who may derive benefit from EGFR or MET-directed therapy. Eligible patients must have progressed after standard-of-care therapy for metastatic disease, be ineligible for, or have declined current standard therapies. The study objectives were to evaluate the feasibility of administration, safety, and PK of a low concentration formulation, 50 mg/mL of amivantamab ± rHuPH20 (Part 1) and a high concentration formulation, 160 mg/mL of amivantamab ± rHuPH20 (Part 2). Patients in Part 1 and Part 2 received the currently approved dosage of amivantamab, 1050 mg (1400 mg for bodyweight ≥80 kg) SC (weekly for the first 4 weeks and every other week thereafter). This study also evaluated administering the full dose of amivantamab on the first day. Results: The full safety, PK, bioavailability, and receptor occupancy data of patients enrolled in Part 1 (n=16) and Part 2 (n=17) will be presented. Compared to IV administration, initial SC experience demonstrates the co-formulation of high concentration amivantamab with rHuPH20 shortened the needed infusion time to less than 5 minutes, with initial bioavailability of approximately 65% of IV administration. Saturation of soluble free EGFR and MET was achieved after the first SC dose. The incidence of IRRs was 18.2%, with all events of grade 1-2 severity. The full amivantamab SC dose was safely given at first administration to 14 patients, potentially obviating the need for split dosing. Conclusions: Initial SC amivantamab ± rHuPH20 was well tolerated with improvements in time and ease of administration and associated with a meaningful reduction in IRRs, eliminating the need for split dosing compared with IV administration. Higher SC dose levels and alternative dosing schedules are being explored. Citation Format: Matthew G. Krebs, Melissa L. Johnson, Byoung Chul Cho, Se-Hoon Lee, Rachel Kudgus-Lokken, Donna Zemlickis, Anna Mitselos, Eileen Berkay, Joshua M. Bauml, Roland E. Knoblauch, Peter Hellemans, Anna Minchom. Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: Initial safety and pharmacokinetic results from the PALOMA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT198.

Intestinal failure-associated liver disease (IFALD) remains one of the most common and serious complications of parenteral nutrition (PN), causing a wide spectrum of hepatic manifestations from steatosis and mild cholestasis to portal hypertension and end-stage liver failure. The prevalence of IFALD depends on the diagnostic criteria and ranges from 4.3% to 65%. Moreover, many factors are shown to contribute to its development, including nutrient deficiencies, toxicity of PN, infections, and alterations of bile acid metabolism and gut microbiota. Prevention and management of IFALD aim at ameliorating or eliminating the risk factors associated with IFALD. The use of PN formulations with a lower ratio omega-6-to-omega-3 polyunsaturated fatty acids, cycle PN, optimization of enteral stimulation and prevention and early treatment of infections constitute the main therapeutic targets. However, failure of improvement and severe IFALD with end-stage liver failure should be considered as the indications of intestinal transplantation. The aim of this review is to provide an update of the epidemiology, pathophysiology, and diagnosis of IFALD in the adult population as well as to present a clinical approach of the therapeutic strategies of IFALD and present novel therapeutic targets.

Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B‐cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single‐dose ibrutinib plus single‐dose midazolam). Systemic induction was assessed at steady‐state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) were derived using linear mixed‐effects models (90% confidence interval within 80%‐125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady‐state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion.

Celiac disease (CD) is a chronic intestinal immune-mediated disease occurring in genetically susceptible individuals who are exposed to gluten. Although it primarily affects the small intestine, CD has been associated with a wide spectrum of extraintestinal manifestations, including thromboembolism and cardiovascular events. The risk of ischemic stroke, myocardial infarction, and thromboembolism, such as deep vein thrombosis and pulmonary embolism, is higher in patients with CD, while there is accumulating evidence that gluten-free diet in CD patients decreases the risk of these complications. The pathogenetic mechanism of increasing hypercoagulability in CD is multifactorial and involves hyperhomocysteinemia due to malabsorption of vitamins B12, B6, and folic acid; endothelial dysfunction; acceleration of atherosclerosis; chronic inflammation; thrombocytosis; and thrombophilia. Therefore, in cases of thromboembolic complications and cardiovascular disease of obscure etiology, clinicians' awareness of possible celiac disease is warranted.

Background Small bowel capsule endoscopy (SBCE) enables the direct visualisation of the entire small bowel (SB) mucosa and the application of the Lewis score allows the reliable assessment of the SB mucosal inflammatory activity in Crohn’s disease (CD) patients. The study aim was to investigate the association of disease location, extent and inflammatory activity in CD patients with the use of SBCE Methods Retrospective study of 80 consecutive patients with an established CD that underwent SBCE in the Gastroenterology Department of the University Hospital of Ioannina between January 2007 and October 2019, for the evaluation of disease extent and disease activity. Results Fifty-one patients had evidence of endoscopic disease activity. In 30 of these patients (58.8%), the disease was located in the ileum and proximal SB, whereas in 20 patients (39.2%) the disease was located solely in the terminal ileum. In one patient (2%) treated with adalimumab, the disease was located solely in the jejunum. Eight patients (15.7%) had evidence of disease activity in the upper GI. All patients with upper GI disease activity demonstrated proximal SB disease involvement. The median Lewis score in patients with proximal CD was 1350 (mean 1666.3; Std 1343) median) against 458 (mean 1548,6; Std 1751) in patients with disease located in the ileum (p = 0.10). Conclusion In our study, proximal small bowel disease involvement was present in >50% of CD patients. Upper GI involvement was associated with extensive SB disease. Patients with proximal SB CD demonstrated a higher median Lewis score compared with those with CD located solely in the terminal ileum.

Background Small bowel capsule endoscopy (SBCE) is widely used for various indications in patients with established Crohn’s disease (CD). Our aim was to investigate whether SBCE can lead to changes in the therapeutic management of CD patients. Methods Retrospective analysis of prospectively collected data [September 2003 - September 2019] from patients with established CD subjected to SBCE in two tertiary referral centres for inflammatory bowel diseases. All patients were tested with the Pillcam SB. Findings consistent with small bowel CD involvement were the presence of aphthoid or larger ulcers with or without inflammation of the adjacent mucosa. Results In total, 839 patients [median age (range) 36 (17–78) years, 471 (56.41%) men, median disease duration 6 years] diagnosed with CD according to established criteria underwent SBCE in the participating centres for the evaluation of disease extent and mucosal healing or the investigation of clinical relapse or iron deficiency anaemia. Based on ileo-colonoscopy findings disease location was documented in 618 patients (73.65%) as follows: colitis in 219 (26.10%), ileo-colitis in 253 (30.15%), and terminal ileitis in 146 (17.40%) patients; in contrast, full disease location was not documented in 221/839 (26.34%) patients who had colonic involvement but the ileocaecal valve could not be intubated. In the latter group, SBCE revealed small bowel involvement in 96 (43.43%) patients. In addition, SBCE revealed more proximal lesions in 105/618 (16.99%) patients with ileo-colonoscopy documented colitis, ileo-colitis or terminal ileitis. These findings led to a change in therapeutic management in 98 patients (11.68%): 36 patients (4.29%) received biologics, 21 patients (2.50%) received intensified doses of or changed the administered biologic, 39 patients (4.64%) received corticosteroids and/or conventional immunosuppressants and 2 patients (0.23%) underwent surgery. Therapeutic management changes were commoner in patients in whom small bowel lesions were found during SBCE and in whom the terminal ileum had not been examined during colonoscopy (57/96 patients vs. 41/105, p = 0.003]. Capsule retention occurred in 9 patients (1.07%) and passed after administration of corticosteroids (n = 6), or the capsule was retrieved with push enteroscopy (n = 1) or surgery (n = 1). Conclusion SBCE is a valuable tool in the management of patients with established CD, especially in those whom the terminal ileum has not been examined during the preceding colonoscopy.

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir. ispartof: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY vol:63 issue:4 ispartof: location:United States status: published

TPS3150 Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody with immune cell-directing activity, targets activating/resistance EGFR mutations and MET mutations/amplifications. Amivantamab has demonstrated antitumor activity in patients (pts) with EGFR-mutant NSCLC and also in pts with EGFR tyrosine kinase inhibitor-resistant disease. The recommended phase 2 dose (RP2D) is 1050 mg (1400 mg, ≥80 kg) administered as intravenous (IV) infusions weekly (QW) for the first 28-day cycle and every other week (Q2W) thereafter. A subcutaneous (SC) formulation of amivantamab has the potential to reduce pt and physician burden by reducing administration time. The safety and pharmacokinetics (PK) of amivantamab administered SC ± recombinant human hyaluronidase (rHuPH20) will be evaluated. Methods: PALOMA is an ongoing phase 1b dose escalation study of amivantamab SC in pts with advanced solid tumors that may derive benefit from EGFR or MET-directed therapy (NCT04606381). Pts must have progressed on standard of care therapy for metastatic disease, be ineligible for, or have refused current standard therapies. The primary endpoints are trough concentration at the end of QW dosing and safety of SC administration. The objective of part 1 is to evaluate the feasibility, safety, and PK of SC administration of a low concentration (50 mg/mL) formulation of amivantamab alone (Ami-LC) or admixed with rHuPH20 (Ami-LC-MD). Approximately 8 pts will be enrolled to receive either 1050/1400 mg amivantamab SC using Ami-LC-MD (Cohort 1a) or Ami-LC (Cohort 1b) QW in cycle 1 and Q2W thereafter. The objective of part 2 is to evaluate the safety and PK of SC administration of a high concentration (160 mg/mL) formulation of amivantamab alone (Ami-HC) or with rHuPH20 (Ami-HC-CF) and to determine a dose, schedule, and formulation for SC administration that achieves similar exposure as observed at the RP2D of amivantamab IV, with acceptable safety. Pts enrolled in part 2 will initially receive 1050/1400 mg amivantamab SC using Ami-HC-CF in Cohort 2a or Ami-HC in Cohort 2b. ≤10 pts may be enrolled in either cohort. Additional cohorts of ≤10 pts may be enrolled to support dose, schedule, and formulation selection as guided by safety and PK observations in earlier cohorts. To mitigate infusion related reactions (IRR), medication with steroid, paracetamol, and antihistamine will be given pre-infusion and as clinically indicated post-infusion. Safety assessments include monitoring adverse events, laboratory abnormalities, vital signs, IRR, and injection site reactions. Blood samples will be collected to assess PK, pharmacodynamics, and immunogenicity. A Study Evaluation Team composed of investigators and sponsor representatives will review safety and PK data to make decisions about dose escalation and cohort expansion throughout the conduct of the study. Clinical trial information: NCT04606381.