J Intensive Care Med
August 2024
The rapidly advancing field of cancer therapeutics has led to increased longevity among cancer patients as well as increasing complexity of cancer-related illness and associated comorbid conditions. As a result, institutions and organizations that specialize in the in-patient care of cancer patients have similarly evolved to meet the constantly changing needs of this unique patient population. Within these institutions, the intensive care units that specialize in the care of critically ill cancer patients represent an especially unique clinical resource.
View Article and Find Full Text PDFUterine carcinosarcoma is a rare, aggressive tumor with several cases in the literature reporting cardiac tumor thrombus involvement. In this case report, we describe a 72-year-old female with a history of uterine carcinosarcoma, who presented with extensive thrombus in the Inferior Vena Cava (IVC) and right atrium. The patient underwent an aspiration thrombectomy which aided in intravascular debulking of the thrombus.
View Article and Find Full Text PDFIntensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure.
View Article and Find Full Text PDFThe purpose of this study was to determine whether retention of a post-pyloric Dobhoff tube (DHT) in position to serve as a visual guide through the pylorus during gastrojejunostomy (GJ) tube placement results in a reduction in fluoroscopy time, procedure time, and estimated radiation dose. A retrospective study evaluated patients who underwent GJ tube placement or gastric to GJ conversion from January 1, 2017, to April 1, 2021. Demographic and procedural data were collected, and results were evaluated using descriptive statistics and hypothesis testing through an unpaired Student's t-test.
View Article and Find Full Text PDFExpert Rev Endocrinol Metab
November 2021
Introduction: Despite considerable progress in diabetes treatment, prevalence of nocturnal hypoglycemia in type 1 diabetes mellitus (T1DM) and advanced insulin treated type 2 diabetes mellitus (T2DM) remains high.
Areas Covered: The present manuscript describes the prevalence of night-time hypoglycemia as reported in observational and randomized controlled trials. Factors that affect the risk of hypoglycemia are highlighted.
Introduction: DPP-4 inhibitors have pleomorphic effects that extend beyond the anti-hyperglycemic labeled use of the drug. DPP-4 inhibitors have demonstrated promising renal protective effects in T2DM and T1DM and protective effects against immune destruction of pancreatic beta-cells in T1DM.
Areas Covered: The efficacy of DPP-4 inhibitors in the treatment of diabetic kidney disease and possible adjunct with insulin in the treatment of T1DM to preserve beta-cell function.
T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs.
View Article and Find Full Text PDFBackground & Aims: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy.
View Article and Find Full Text PDFThe purpose of this study was to evaluate the pharmacokinetics (PK) of anti-oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half-life (T ), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group).
View Article and Find Full Text PDFPurpose: The purpose of this study is to evaluate the pharmacokinetics, immunogenicity, safety, and tolerability of guselkumab, a human monoclonal antibody with high affinity and specificity for binding to interleukin-23.
Methods: In this first-in-human, phase 1, randomized study, a single intravenous (IV; 0.03-10 mg/kg) or subcutaneous (SC; 10-300 mg) dose of guselkumab was administered to 47 healthy subjects, and a single SC dose (placebo, 10, 30, 100, 300 mg) was administered to 24 patients with moderate-to-severe psoriasis.
Background And Aims: To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies.
Methods: We analysed golimumab PK and ER data of patients with moderate-to-severe UC from the PURSUIT-subcutaneous induction [N = 1064] and maintenance [N = 464] studies. Induction analyses evaluated serum golimumab concentration [SGC] and efficacy data through Week [wk] 6 following subcutaneous doses at wk0 and wk2; maintenance analyses assessed data through wk54 following 4-weekly dosing.
This therapeutic protein-drug interaction study evaluated the disease-mediated effect of sirukumab (anti-interleukin 6 [anti-IL-6] monoclonal antibody) on the pharmacokinetics of the cytochrome P450 (CYP) probe substrates midazolam (CYP3A), omeprazole (CYP2C19), warfarin (CYP2C9), and caffeine (CYP1A2) in patients with active rheumatoid arthritis (RA). Twelve patients with C-reactive protein (CRP) ≥ 8.0 mg/L at screening received oral administration of a CYP probe cocktail consisting of 0.
View Article and Find Full Text PDFCancer Chemother Pharmacol
May 2015
Purpose: Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. CRP suppression is an indirect measurement of IL-6 activity. Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD).
View Article and Find Full Text PDFThe pharmacokinetics (PK) of biologic therapeutics, especially monoclonal antibodies (mAbs), in monkeys generally presents the most relevant predictive PK information for humans. However, human mAbs, xenogeneic proteins to monkeys, are likely to be immunogenic. Monkeys previously treated with a human mAb (non-naïve) may have developed antidrug antibodies (ADAs) that cross-react with another test mAb in subsequent studies.
View Article and Find Full Text PDFImmune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-α agents (anti-TNFα), for the treatment of RA and Crohn's disease (CD).
View Article and Find Full Text PDFCNTO 5825 is a human anti-interleukin-13 (IL-13) monoclonal antibody (mAb) that inhibits binding of human IL-13 to IL-13Rα1 and IL-13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non-clinical PK data in order to select the right and safe doses for first-in-human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.
View Article and Find Full Text PDFPurpose: This Phase 1 pharmacokinetic (PK) comparability study in healthy subjects was performed to compare the PK properties and tolerability of single-dose golimumab 100 mg delivered subcutaneously by an autoinjector device or by a standard needle and syringe that had been used for the subcutaneous (SC) delivery of golimumab in pivotal Phase 3 studies.
Methods: Healthy male subjects were randomly assigned to receive a single injection of SC golimumab 100 mg using either the autoinjector or a standard needle and syringe. The PK parameters of golimumab were calculated using noncompartmental analysis.
Background & Aims: We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis.
Methods: We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses.
Siltuximab, a monoclonal antibody (mAb) against interleukin (IL-6), is under development by Janssen Research & Development, LLC. During early clinical development, siltuximab was produced in a murine Sp2/0 myeloma cell line. The production cell line was switched to stably transfected Chinese hamster ovary (CHO) cell line for subsequent clinical development.
View Article and Find Full Text PDFFor therapeutic monoclonal antibodies (mAbs) against soluble ligands, the free ligand level can, theoretically, be used as a surrogate for efficacy. However, it can be extremely challenging technically to measure free ligand level in the presence of an excessive amount of antibody-ligand complex. The interplay among such mAbs, ligands, and the downstream pharmacodynamic (PD) effects has not been well defined.
View Article and Find Full Text PDFA parallel study design with a large number of subjects has been a typical path for pharmacokinetic (PK) biocomparability assessment of biotherapeutics with long half-lives and immunogenic propensity, for example, monoclonal antibodies (mAb). A recently published innovative bioanalytical method that can quantify mAb produced from two different cell lines in the same sample opened an avenue to exploring a simultaneous crossover study design for PK biocomparability assessment of biotherapeutics. Siltuximab, a chimeric IgG1 mAb-targeting interleukin-6, was studied as an example.
View Article and Find Full Text PDFBackground: To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC).
Methods: This phase 3, randomized, open-label multicenter study enrolled 60 children (6-17 yr) with moderate-to-severely active UC (Mayo score, 6-12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6.
Background And Objectives: Golimumab is an anti-tumor necrosis factor-α human immunoglobulin G1κ monoclonal antibody that is efficacious for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in adults. The objective of this study was to assess the pharmacokinetic characteristics of golimumab in healthy male Chinese subjects following a single subcutaneous (SC) administration of golimumab 50 or 100 mg. The safety, tolerability, and immunogenicity of a single SC administration of golimumab in Chinese subjects were also evaluated.
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