Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies
Abstract Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment fo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 5, 2015 Category: Drugs & Pharmacology Source Type: research

Modeling energy intake by adding homeostatic feedback and drug intervention
Abstract Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction. The paper describes a model with the capability to capture physiological counter-regulatory feedback actions triggered by energy imbalances. This feedback is general as it handles tolerance to both increases and decreases in EI, and works in both...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic–pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice
The objective of this study was to develop a PK–PD model to accurately simulate hepatic ASO concentration and its efficacy from plasma ASO concentration. After single subcutaneous administration of an ASO targeting hepatic apolipoprotein B (Apo-B) mRNA to mice, the ASO was absorbed rapidly and showed biphasic decline with time from the plasma and liver (t1/2: 1–3 and 81–183 h, Tmax: 0.25–0.50 and 4–8 h). After administration, hepatic Apo-B mRNA and plasma total cholesterol began decreasing at 4–8 and 8–24 h, and their Tmax values were observed at 24–72 and 72&n...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 7, 2014 Category: Drugs & Pharmacology Source Type: research

Modeling and simulation of the exposure–response and dropout pattern of guanfacine extended-release in pediatric patients with ADHD
Abstract Guanfacine extended-release (GXR) is a selective α2A-adrenergic receptor agonist approved in the United States for once-daily administration for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents ages 6–17 years old either as monotherapy or adjunctive to stimulant medications. This analysis integrates exposure–response, placebo, and dropout data from 10 clinical trials that used GXR in adolescents and children with ADHD. In these trials, the ADHD Rating Scale-IV (ADHD RS-IV) score was collected longitudinally within patients over the course ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 6, 2014 Category: Drugs & Pharmacology Source Type: research

Simulation studies on the estimation of total area under the curve in the presence of right-tailed censoring
Abstract The effect of extrapolated area (%AUCextrap) on estimating mean AUCinf in a simulated single-dose clinical trial was examined. Concentration–time (C–t) profiles from 12 to 36 subjects for 1- and 2-compartment models after single dose administration were simulated with increasing right-tailed censoring. Each subject’s %AUCextrap and AUCinf was calculated using eight different methods, including noncompartmental analysis (NCA), population-based methods, and maximum likelihood (ML) accounting for censoring. Each method’s geometric mean AUCinf and percent relative error (PRE) from ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 31, 2014 Category: Drugs & Pharmacology Source Type: research

In vitro simulation of in vivo pharmacokinetic model with intravenous administration via flow rate modulation
Abstract The aim of this paper was to propose a method of flow rate modulation for simulation of in vivo pharmacokinetic (PK) model with intravenous injection based on a basic in vitro PK model. According to the rule of same relative change rate of concentration per unit time in vivo and in vitro, the equations for flow rate modulation were derived using equation method. Four examples from literature were given to show the application of flow rate modulation in the simulation of PK model of antimicrobial agents in vitro. Then an experiment was performed to confirm the feasibility of flow rate modulation method usi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 29, 2014 Category: Drugs & Pharmacology Source Type: research

A review of quantitative modeling of B cell responses to antigenic challenge
Abstract A key role of B cells in the mammalian immune response is the generation of antibodies that serve to protect the organism against antigenic challenges. The same process may also be detrimental in the context of autoimmunity. Several modeling approaches have been applied to this aspect of the immune response, from predicting potential epitopes to describing B cells progress through developmental models and simulating antibody production. Here we review some of the modeling techniques, and summarize models that describe different activation mechanisms for B cells, including T cell dependent and independent ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 19, 2014 Category: Drugs & Pharmacology Source Type: research

FLT3 and CDK4/6 inhibitors: Signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia
In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK,...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 19, 2014 Category: Drugs & Pharmacology Source Type: research

Predicted impact of various clinical practice strategies on cardiovascular risk for the treatment of hypertension: a clinical trial simulation study
Abstract Hypertension control rate in the US is low with the current clinical practice (JNC 7) and cardiovascular disease (CVD) remain is the leading cause of morbidity and mortality. A 6-month clinical trial simulation case study testing different virtual clinical practice strategies was performed in an attempt to increase the control rate. The CVD risk was calculated using the Framingham CVD risk model at baseline and 6 months post-treatment. The estimated CVD events for the baseline patient sample without any treatment was 998 (95 % CI: 967–1,026) over 6 months in 100,000 patients. Treating...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 18, 2014 Category: Drugs & Pharmacology Source Type: research

Searching for an optimal AUC estimation method: a never-ending task?
Abstract An effective method of construction of a linear estimator of AUC in the finite interval, optimal in the minimax sense, is developed and demonstrated for five PK models. The models may be given as an explicit C(t) relationship or defined by differential equations. For high variability and rich sampling the optimal method is only moderately advantageous over optimal trapezoid or standard numerical approaches (Gauss-Legendre or Clenshaw-Curtis quadratures). The difference between the optimal estimator and other methods becomes more pronounced with a decrease in sample size or decrease in the variability....
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 15, 2014 Category: Drugs & Pharmacology Source Type: research

Optimal clinical trial design based on a dichotomous Markov-chain mixed-effect sleep model
Abstract D-optimal designs for discrete-type responses have been derived using generalized linear mixed models, simulation based methods and analytical approximations for computing the fisher information matrix (FIM) of non-linear mixed effect models with homogeneous probabilities over time. In this work, D-optimal designs using an analytical approximation of the FIM for a dichotomous, non-homogeneous, Markov-chain phase advanced sleep non-linear mixed effect model was investigated. The non-linear mixed effect model consisted of transition probabilities of dichotomous sleep data estimated as logistic functions...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 12, 2014 Category: Drugs & Pharmacology Source Type: research

Modeling and simulation for medical product development and evaluation: highlights from the FDA-C-Path-ISOP 2013 workshop
Abstract Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA’s 2011 Strategic Plan for Regulatory Science [Appendix]. In an effort to support and advance model-informed medical-product development (MIMPD), the Critical Path Institute (C-Path) [www.c-path.org], FDA, and International Society of Pharmacomet...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 7, 2014 Category: Drugs & Pharmacology Source Type: research

Clinical endpoint sensitivity in rheumatoid arthritis: modeling and simulation
Abstract The commonly used efficacy endpoints in Rheumatoid Arthritis (RA) clinical trials are American College of Rheumatology 20 % improvement criteria (ACR20), ACR50, and ACR70 response rates, and the 28-joint disease activity score (DAS28). Longitudinal models to quantitate the exposure–response relationships for ACRs and DAS28 score were developed for four biologics used for the management of RA. The models were then used to simulate the clinical outcome at various time points following different treatment regimens. Discriminative sensitivity of these endpoints was assessed using a power analysis. ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 5, 2014 Category: Drugs & Pharmacology Source Type: research

Modeling cancer-immune responses to therapy
Abstract Cancer therapies that harness the actions of the immune response, such as targeted monoclonal antibody treatments and therapeutic vaccines, are relatively new and promising in the landscape of cancer treatment options. Mathematical modeling and simulation of immune-modifying therapies can help to offset the costs of drug discovery and development, and encourage progress toward new immunotherapies. Despite advances in cancer immunology research, questions such as how the immune system interacts with a growing tumor, and which components of the immune system play significant roles in responding to immunothe...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 4, 2014 Category: Drugs & Pharmacology Source Type: research

Continuous-time Markov modelling of flexible-dose depression trials
Abstract The aim of this paper is to provide a systematic methodology for modelling longitudinal data to be used in contexts of limited or even absent knowledge of the physiological mechanism underlying the disease time course. Adopting a system-theoretic paradigm, a population response model is developed where the clinical endpoint is described as a function of the patient’s health state. In particular, a continuous-time stochastic approach is proposed where the clinical score and its time-derivative summarize the patient’s health state affected by a random term accounting for exogenous unpredictable ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 4, 2014 Category: Drugs & Pharmacology Source Type: research

Viral kinetic modeling: state of the art
Abstract Viral kinetic (VK) modeling has led to increased understanding of the within host dynamics of viral infections and the effects of therapy. Here we review recent developments in the modeling of viral infection kinetics with emphasis on two infectious diseases: hepatitis C and influenza. We review how VK modeling has evolved from simple models of viral infections treated with a drug or drug cocktail with an assumed constant effectiveness to models that incorporate drug pharmacokinetics and pharmacodynamics, as well as phenomenological models that simply assume drugs have time varying-effectiveness. We also...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2014 Category: Drugs & Pharmacology Source Type: research

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