A computational framework for complex disease stratification from multiple large-scale datasets.

Background: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states.

Safety and pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy male volunteers: A randomized phase I study.

Interleukin-6 (IL-6) is implicated in the pathophysiology of several inflammatory conditions. Olokizumab, a humanized anti-IL-6 monoclonal antibody, selectively blocks the final assembly of the IL-6 signaling complex. A randomized, double-blind, placebo-controlled, phase I dose-escalation study assessed the safety and tolerability of escalating single doses of olokizumab administered intravenously (iv) or subcutaneously (sc) to 67 healthy male volunteers.

Model-Based Optimal Design and Execution of the First-Inpatient Trial of the Anti-IL-6, Olokizumab.

The first-in-patient study for olokizumab (OKZ) employed model-based, optimal design and adaptive execution to define the concentration-C-reactive protein (CRP) suppression response. Modeling and exploratory statistics activities involved: reverse engineering of first-in-class (tocilizumab) pharmacokinetic/pharmacodynamic (PK/PD) models, adaptation of models to OKZ with a priori knowledge and preclinical data translation, application of multidimensional Desirability Index for optimal study design, sample size reestimation based on new information, optimization of second study part via Bayesian analysis of interim data, and interim and final analysis for PK/PD objective attainment. Design work defined a dose window (0.

Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study.

Objectives: The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.

Methods: Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W.

Leveraging systems biology approaches in clinical pharmacology.

Computational modeling has been adopted in all aspects of drug research and development, from the early phases of target identification and drug discovery to the late-stage clinical trials. The different questions addressed during each stage of drug R&D has led to the emergence of different modeling methodologies. In the research phase, systems biology couples experimental data with elaborate computational modeling techniques to capture lifecycle and effector cellular functions (e.

Partitioning, diffusivity and clearance of skin permeants in mammalian dermis.

The partition coefficients (K(de)) and diffusivities (D(de)) of compounds in mammalian dermis were examined through an analysis of in vitro permeation data obtained from the literature combined with experimental results with the test permeant, (3)H-testosterone. The literature data involved 26 compounds ranging in molecular weight from 18 to 476 Da and four species-human, guinea pig, rat and mouse. Testosterone was studied by permeation and desorption measurements employing excised human dermis in the presence and absence of external serum albumin.

A geometrical model of dermal capillary clearance.

A new microscopic model is developed to describe the dermal capillary clearance process of skin permeants. The physiological structure is represented in terms of a doubly periodic array of absorbing capillaries. Convection-dominated transport in the blood flow within the capillaries is coupled with interstitial diffusion, the latter process being quantified via a slender-body-theory approach.

Glucose partition coefficient and diffusivity in the lower skin layers.

Purpose: This work aims to estimate the diffusivity and partitioning of glucose in the dermis and the viable epidermis of human skin.

Methods: The partition coefficient of glucose between phosphate-buffered saline and dermis, tape-stripped epidermis (TSE), stratum corneum (SC), and split-thickness skin, was measured in vitro using human cadaver skin. Glucose permeability across dermis and tape-stripped split-thickness skin (TSS) was measured using side-by-side diffusion cells.

Dermal capillary clearance: physiology and modeling.

Substances applied to the skin surface may permeate deeper tissue layers and pass into the body's systemic circulation by entering blood or lymphatic vessels in the dermis. The purpose of this review is an in-depth analysis of the dermal clearance/exchange process and its constituents: transport through the interstitium, permeability of the microvascular barrier and removal via the circulation. We adapt an 'engineering' viewpoint with emphasis on quantifying the dermal microcirculatory physiology, providing the theoretical framework for the physics of key transport processes and reviewing the available computational clearance models in a comparative manner.

Distributed diffusion-clearance model for transient drug distribution within the skin.

Quantitative predictions of molecular transport rates through the skin are key to the development of topically applied and transdermally delivered drugs, as well as risk assessment associated with dermal exposure. Most research to date has focused on correlations for the permeability of the stratum corneum, and transient diffusion models that oversimplify vascular clearance processes in terms of a perfect-removal boundary condition at an artificially introduced lower boundary. Considerations of the spatially distributed nature and action of blood vessels have usually been limited to the steady-state case.