Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1β monoclonal antibody

Canakinumab is a high-affinity human monoclonal anti-interleukin-1β (IL-1β) antibody of the IgG1/κ isotype designed to bind and neutralize the activity of human IL-1β, a pro-inflammatory cytokine. Canakinumab is currently being investigated on the premise that it would exert anti-inflammatory effects on a broad spectrum of diseases, driven by IL-1β. This paper focuses on the analysis of the pharmacokinetic and pharmacodynamic data from the canakinumab clinical development programme, describing results from the recently approved indication for the treatment of cryopyrin-associated periodic syndromes (CAPS) under the trade name ILARIS?, as well as diseases such as rheumatoid arthritis, asthma and psoriasis. Canakinumab displays pharmacokinetic properties typical of an IgG1 antibody. In a CAPS patient weighing 70?kg, slow serum clearance (0.174?L/day) was observed with a low total volume of distribution at steady state (6.0?L), resulting in a long elimination half-life of 26 days. The subcutaneous absolute bioavailability was high (70%). Canakinumab displays linear pharmacokinetics, with a dose-proportional increase in exposure and no evidence of accelerated clearance or time-dependent changes in pharmacokinetics following repeated administration was observed. The pharmacokinetics of canakinumab in various diseases (e.g. CAPS, rheumatoid arthritis, psoriasis or asthma) are comparable to those in healthy individuals. No sex- or age-related pharmacokinetic differences were observed after correction for body weight. An increase in total IL-1β was observed in both healthy subjects and all patient populations following canakinumab dosing, reflecting the ability of canakinumab to bind circulating IL-1β. The kinetics of total IL-1β along with the pharmacokinetics of canakinumab were characterized by a population-based pharmacokinetic-binding model, where the apparent in vivo dissociation constant, signifying binding affinity of canakinumab to circulating IL-1β, was estimated at 1.07?±?0.173?nmol/L in CAPS patients. During development of canakinumab a cell line change was introduced. Pharmacokinetic characterization was performed in both animals and humans to assure that this manufacturing change did not affect the pharmacokinetic/pharmacodynamic properties of canakinumab.     

Bioluminescence based in vivo screening technologies

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Highlights? Bioluminescence imaging, a cell-based tool for high-throughput screening. ? Luciferase biosensors to study gene expression and protein–protein interactions. ? Bioluminescent microscopy for imaging intracellular dynamics and heterogeneity. ? BLI screening, a single format assay for both mammalian cell and animal model.     

A survey of attitude of frontline clinicians and nurses towards adverse events

Background

It is often said that doctors are only human. However, technological wonders, apparent precision of diagnostic tests and scientific innovation have created an expectation of perfection from medical science. Patient safety and prevalence of adverse events on the hospital floor have become issues of serious concern for the healthcare environment.

Method

The study had cross-sectional design, done over a period of one year at a teaching medical college and its affiliated hospitals. The study instrument was an anonymous, voluntary 5-point Likert scaled questionnaire and study sample was selected by simple random sampling into two groups of front-line clinicians (n = 175) and nurses (n = 60). The questionnaire was analysed for its reliability, construct and content validity. Subsequently, the data was entered into an Excel Spreadsheet and further analysed by statistical software SPSS version 16.

Results

Total of 175 front-line clinicians and 60 nurses completed the survey for response rate of 96%. The study instrument was suitably validated for its psychometric properties. Statistically significant differences were observed between the two study samples across certain attitudinal statements, the important ones being responsibility for reporting and comfort level towards disclosing adverse events. Surgical site infections, Medication errors and Patient Falls were the commonly observed adverse events and lack of communication among team members was identified as a major factor leading to adverse events.

Conclusion

Effective attitude-based interventions need to be developed, where the attitude and culture of front-line healthcare workers can be explicitly targeted for inducing desirable behavioural changes towards improved patient safety.     

Predictive Mechanistic Model of Creep Response of Single-Layered Pressure-Sensitive Adhesive (PSA) Joints

This paper explores the uniaxial tensile creep response of acrylic-based pressure-sensitive adhesive (PSA), which exhibits a unique multi-phase creep response that does not have the classical steady-state region due to multiple transitions caused by several competing mechanisms: (i) cavity nucleation and growth in the interior of the adhesive material of the PSA system, as well as at the interfaces between the PSA and the substrate; (ii) fibrillation of the bulk adhesive, and (iii) interfacial mechanical locking between the adhesive and the bonding substrate. This results in multiple regimes of strain hardening and strain softening, evidenced by multiple regions of steady-state creep, separated by strong transitions in the creep rates. This complex, multi-phase, nonlinear creep response cannot be described by conventional creep constitutive models commonly used for polymers in commercial finite element codes. Accordingly, based on the empirical uniaxial tensile creep response and the mechanisms behind it, a new mechanistic model was proposed. This is capable of quantitatively capturing the characteristic features of the multiphase creep response of single-layered PSA joints as a function of viscoelastic bulk properties and free energy of the PSA material, substrate surface roughness, and interfacial surface energy between the adhesive and substrate. This is the first paper to present the modeling approach for capturing unique multi-phase creep behavior of PSA joint under tensile loading.     

Association of progesterone receptor gene polymorphism with male infertility and clinical outcome of ICSI

Purpose

To investigate the association of Progesterone Receptor (PR) gene variations and male infertility

Methods

DNA extraction, PCR and sequencing of PR gene, PROGINS insertion by PCR. Association of the variations with seminal parameters and outcomes of ICSI.

Results

Four known SNPs in the PR gene were identified in the study of which three (rs3740753, rs1042838, rs104283) were co-inherited and in complete linkage disequilibrium with the PROGINS Alu insertion. There were no differences in their frequencies between fertile and infertile males. The rs2020880 was found at a very low frequency only in the controls but not in the infertile subjects. The sperm counts, fertilization rate, embryo quality or pregnancy rates were not different in individuals with or without PROGINS allele.

Conclusion

PR gene alterations are not associated with male infertility or ICSI outcome.     

Vascular patterning and permeability in prostate cancer models with differing osteogenic properties

Bone metastasis is a major cause of morbidity and mortality in prostate cancer. However, the lack of clinically relevant models hinders our understanding of the disease as well as development of effective therapies and imaging approaches. We used noninvasive MRI, histology and micro CT to further characterize the newly established prostate cancer bone metastases-derived model MDA-PCa-118b, and to compare it to the well-established PC-3MM2 model with regard to bone structure and vascular patterning. The PC-3MM2 model is highly osteolytic whereas the MDA-PCa-118b model shows a robust osteoblastic reaction, as often seen in clinical cases. Macromolecular contrast enhanced MRI revealed differences in vascular permeability patterns, which appeared peripheral for PC-3MM2 and nodular for MDA-PCa-118b, matching the microscopic cellular composition of each model: PC-3MM2 exclusively recruits endothelial cells to form thin tumor-core blood vessels and enlarged, leaky peripheral vessels, whereas MDA-PCa-118b also recruits bone-forming cells and pericytes such that small tumor nests are encircled with leaky vessels and embedded in bone-like tissue dotted with pericyte-covered vessels. Despite these structural differences, vascular permeability was reduced in both tumor models by either imatinib or SU10944 treatment. This study highlights the importance of clinically relevant osteogenic models of human prostate cancer and the value of such models not only in enhancing our understanding of tumorigenesis, metastasis and response to therapy, but also for development of appropriate methods for noninvasive imaging of these processes.