Dynamic transcriptional signatures and network responses for clinical symptoms in influenza-infected human subjects using systems biology approaches
Abstract Recent studies demonstrate that human blood transcriptional signatures may be used to support diagnosis and clinical decisions for acute respiratory viral infections such as influenza. In this article, we propose to use a newly developed systems biology approach for time course gene expression data to identify significant dynamically response genes and dynamic gene network responses to viral infection. We illustrate the methodological pipeline by reanalyzing the time course gene expression data from a study with healthy human subjects challenged by live influenza virus. We observed clear differences in t...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2014 Category: Drugs & Pharmacology Source Type: research

Review on modeling anti-antibody responses to monoclonal antibodies
Abstract Monoclonal antibodies (mAbs) represent a therapeutic strategy that has been increasingly used in different diseases. mAbs are highly specific for their targets leading to induce specific effector functions. Despite their therapeutic benefits, the presence of immunogenic reactions is of growing concern. The immunogenicity identified as anti-drug antibodies (ADA) production due to the continuous administration of mAbs may affect the pharmacokinetics (PK) and/or the pharmacodynamics (PD) of mAbs administered to patients. Therefore, the immunogenicity and its clinical impact have been studied by several auth...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2014 Category: Drugs & Pharmacology Source Type: research

Abstracts Accepted for American Conference on Pharmacometrics 2014 (ACoP5)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2014 Category: Drugs & Pharmacology Source Type: research

Modeling T cell responses to antigenic challenge
This article discusses the use of mathematical models for understanding the dynamics of cytotoxic T lymphocyte (CTL) responses against viral infections. Complementing experimental research, mathematical models have been very useful for exploring new hypotheses, interpreting experimental data, and for defining what needs to be measured to improve understanding. This review will start with minimally parameterized models of CTL responses, which have generated some valuable insights into basic dynamics and correlates of control. Subsequently, more biological complexity is incorporated into this modeling framework, examining di...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2014 Category: Drugs & Pharmacology Source Type: research

Program
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2014 Category: Drugs & Pharmacology Source Type: research

The American conference on pharmacometrics 2014 (ACoP5)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2014 Category: Drugs & Pharmacology Source Type: research

An immunology primer for computational modelers
Abstract The immune system is designed to protect an organism from infection and damage caused by a pathogen. A successful immune response requires the coordinated function of multiple cell types and molecules in the innate and adaptive immune systems. Given the complexity of the immune system, it would be advantageous to build computational models to better understand immune responses and develop models to better guide the design of immunotherapies. Often, researchers with strong quantitative backgrounds do not have formal training in immunology. Therefore, the goal of this review article is to provide a brief pr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 20, 2014 Category: Drugs & Pharmacology Source Type: research

Complex pattern of interleukin-11-induced inflammation revealed by mathematically modeling the dynamics of C-reactive protein
Abstract Inflammation underlies many diseases and is an undesired effect of several therapy modalities. Biomathematical modeling can help unravel the complex inflammatory processes and the mechanisms triggering their emergence. We developed a model for induction of C-reactive protein (CRP), a clinically reliable marker of inflammation, by interleukin (IL)-11, an approved cytokine for treatment of chemotherapy-induced thrombocytopenia. Due to paucity of information on the mechanisms underlying inflammation-induced CRP dynamics, our model was developed by systematically evaluating several models for their ability to...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 18, 2014 Category: Drugs & Pharmacology Source Type: research

Computational pharmacology of rifampin in mice: an application to dose optimization with conflicting objectives in tuberculosis treatment
Abstract Dose selection for rifampin in the treatment of active pulmonary tuberculosis (TB) illustrates some of the challenges for dose optimization within multidrug therapies. Rifampin-based anti-TB regimens are often combined with antiretroviral therapies to treat human immunodeficiency virus (HIV) coinfection. The potent cytochrome P450 (CYP) enzyme inducing properties of rifampin give rise to significant drug-drug interactions, the minimization of which by limiting the dose, conflicts with the maximization of bacterial killing by increasing the dose. Such multiple and conflicting objectives lead to a set of tr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 31, 2014 Category: Drugs & Pharmacology Source Type: research

An updated Alzheimer’s disease progression model: incorporating non-linearity, beta regression, and a third-level random effect in NONMEM
Abstract Our objective was to expand our understanding of the predictors of Alzheimer’s disease (AD) progression to help design a clinical trial on a novel AD medication. We utilized the Coalition Against Major Diseases AD dataset consisting of control-arm data (both placebo and stable background AD medication) from 15 randomized double-blind clinical trials in mild-to-moderate AD patients (4,495 patients; July 2013). Our ADAS-cog longitudinal model incorporates a beta-regression with between-study, -subject, and -residual variability in NONMEM; it suggests that faster AD progression is associated with young...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 29, 2014 Category: Drugs & Pharmacology Source Type: research

Agent-based model of fecal microbial transplant effect on bile acid metabolism on suppressing Clostridium difficile infection: an example of agent-based modeling of intestinal bacterial infection
We present an example ABM of CDI (the C. difficile Infection ABM, or CDIABM) to examine fundamental dynamics of the pathogenesis of CDI and its response to treatment with anti-CDI antibiotics and a newer treatment therapy, fecal microbial transplant. The CDIABM focuses on one specific mechanism of potential CDI suppression: commensal modulation of bile acid composition. Even given its abstraction, the CDIABM reproduces essential dynamics of CDI and its response to therapy, and identifies a paradoxical zone of behavior that provides insight into the role of intestinal nutritional status and the efficacy of anti-CDI therapie...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 29, 2014 Category: Drugs & Pharmacology Source Type: research

Modeling the T cell immune response: a fascinating challenge
Abstract The immune system is designed to protect the organism from infection and to repair damaged tissue. An effective response requires recognition of the threat, the appropriate effector mechanism to clear the pathogen and a return to homeostasis with minimal damage to self-tissues. T cells play a central role in orchestrating the immune response at all stages of the response and have been the subject of intense study by both experimental immunologists and modelers. This review examines some of the more critical questions in T cell biology and describes the latest attempts to address those questions using appr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 26, 2014 Category: Drugs & Pharmacology Source Type: research

Impact of aminophylline on the pharmacodynamics of propofol in beagle dogs
This study aimed to characterize pharmacodynamic interaction between propofol and aminophylline. Nine beagle dogs were randomly allocated at the propofol rates of 0.75 (group A), 1.00 (group B), and 1.25 (group C) mg/kg/min. During period 1, propofol only was infused, while during period 2, aminophylline only, at the rate of 0.69 (group A), 1.37 (group B), and 2.62 (group C) mg/kg/h. During periods 3–5, the two drugs were co-administered. The aminophylline infusion rate was 0.69 (period 3), 1.37 (period 4), and 2.62 (period 5) mg/kg/h. The aminophylline was infused from 0 to 30 h, and the propofol was infused at...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 24, 2014 Category: Drugs & Pharmacology Source Type: research

Survey of monoclonal antibody disposition in man utilizing a minimal physiologically-based pharmacokinetic model
In conclusion, this mPBPK model offers a more mechanistic approach for analyzing plasma mAb PK than compartment models and generates parameters providing useful intrinsic distributional and elimination insights for a large number of mAbs that were examined in man. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 22, 2014 Category: Drugs & Pharmacology Source Type: research

Population model of longitudinal FEV1 data in asthmatics: meta-analysis and predictability of placebo response
Abstract Asthma is an obstructive lung disease where the mechanism of disease progression is not fully understood hence motivating the use of empirical models to describe the evolution of the patient’s health state. With reference to placebo response, measured in terms of FEV1 (Forced Expiratory Volume in 1 s), a range of empirical models taken from the literature were compared at a single trial level. In particular, eleven GSK trials lasting 12 weeks in mild-to-moderate asthma were used for the modelling of longitudinal placebo responses. Then, the chosen exponential model was used to carry out an...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 15, 2014 Category: Drugs & Pharmacology Source Type: research

Predicting individual responses to pravastatin using a physiologically based kinetic model for plasma cholesterol concentrations
In conclusion, we have developed a PBK model that is able to accurately describe the effect of pravastatin treatment on plasma cholesterol concentrations and can be used to provide insight in the mechanisms behind individual variation in statin response. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2014 Category: Drugs & Pharmacology Source Type: research