Model reduction in mathematical pharmacology
AbstractIn this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the effects of drug administration across multiple scales. To address the issue of model complexity, we propose the reduction of each type of model separately prior to being linked. We highlight the use of balanced truncation in reducing the linear components of PBPK models, whilst proper lumping is shown to be efficient in reducing typically nonlinear systems biology type models. The overall methodology is demonstrated via two example systems; a model ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 26, 2018 Category: Drugs & Pharmacology Source Type: research

Assessing QT/QTc interval prolongation with concentration-QT modeling for Phase I studies: impact of computational platforms, model structures and confidence interval calculation methods
AbstractModeling the relationship between drug concentrations and heart rate corrected QT interval (QTc) change from baseline (C- ∆QTc), based on Phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies, has been proposed as an alternative to thorough QT studies (TQT), in assessing drug-induced QT prolongation risk. The present analysis used clinical SAD, MAD and TQT study data of an experimental compound , AZD5672, to evaluate the performance of: (i) three computational platforms (linear mixed-effects modeling implemented via PROC MIXED in SAS, as well as in R using LME4 package and linear quantile m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 19, 2018 Category: Drugs & Pharmacology Source Type: research

A comprehensive evaluation of exposure –response relationships in clinical trials: application to support guselkumab dose selection for patients with psoriasis
AbstractGuselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator ’s Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure–response (E–R) modeling analyses, we sought to predict the guselkumab dose–response (D–R) relationship using data from 1459 patients who participated in these trials. A recently developed novel latent-variable Type ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 16, 2018 Category: Drugs & Pharmacology Source Type: research

Drug –physiology interaction and its influence on the QT prolongation-mechanistic modeling study
AbstractThe current study is an example of drug –disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simu lator. Biophysically detailed model of the human cardiac physiology—ten Tusscher ventricular cardiomyocyte cell model—was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Simulated and observed mean QTc values wi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 15, 2018 Category: Drugs & Pharmacology Source Type: research

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development
AbstractCardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 8, 2018 Category: Drugs & Pharmacology Source Type: research

Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors
The objective of this study was  to explore the mitochondrial-mediated cardiotoxic mechanisms of the two selected TKIs. This was achieved experimentally using immortalized human cardiomyocytes, AC16 cells, to investigate dose- and time-dependent cell killing, along with measurements of temporal changes in key signaling proteins i nvolved in the intrinsic apoptotic and autophagy pathways upon exposure to these agents. Quantitative systems pharmacology (QSP) models were developed to capture the toxicological response in AC16 cells using protein dynamic data. The developed QSP models captured well all the various trends ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 14, 2018 Category: Drugs & Pharmacology Source Type: research

Correction to: PK –PD Compass: bringing infectious diseases pharmacometrics to the patient’s bedside
AbstractThe original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 14, 2018 Category: Drugs & Pharmacology Source Type: research

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data
AbstractAmiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants  
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 12, 2018 Category: Drugs & Pharmacology Source Type: research

Evaluation of performance of distributed delay model for chemotherapy-induced myelosuppression
In conclusion, the distributed delay model was deterministically identifiable from typical cytotoxic data. Its performance was modestly better than the classic model with significantly longer running time. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 12, 2018 Category: Drugs & Pharmacology Source Type: research

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens
AbstractTrastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure –response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 10, 2018 Category: Drugs & Pharmacology Source Type: research

Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model
AbstractAmlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug –drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) mod...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 9, 2018 Category: Drugs & Pharmacology Source Type: research

A framework for 2-stage global sensitivity analysis of GastroPlus ™ compartmental models
AbstractParameter sensitivity and uncertainty analysis for physiologically based pharmacokinetic (PBPK) models are becoming an important consideration for regulatory submissions, requiring further evaluation to establish the need for global sensitivity analysis. To demonstrate the benefits of an extensive analysis, global sensitivity was implemented for the GastroPlus ™ model, a well-known commercially available platform, using four example drugs: acetaminophen, risperidone, atenolol, and furosemide. The capabilities of GastroPlus were expanded by developing an integrated framework to automate the GastroPlus graphica...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 8, 2018 Category: Drugs & Pharmacology Source Type: research

Establishing in vitro –in vivo correlation for antibody drug conjugate efficacy: a PK/PD modeling approach
The objective of this manuscript was to establish in vitro –in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as ‘in vitro tumor static concentration’ (TSCin vitro). TSCin vitr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 8, 2018 Category: Drugs & Pharmacology Source Type: research

How to mathematically optimize drug regimens using optimal control
This article gives an overview of a technique calledoptimal control, which is used to optimize real-world quantities represented by mathematical models. I include background information about the historical development of the technique and applications in a variety of fields. The main focus here is the application to diseases and therapies, particularly the optimization of combination therapies, and I highlight several such examples. I also describe the basic theory of optimal control, and illustrate each of the steps with an example that optimizes the doses in a combination regimen for leukemia. References are provided fo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 6, 2018 Category: Drugs & Pharmacology Source Type: research

Structural identifiability for mathematical pharmacology: models of myelosuppression
AbstractStructural identifiability is an often overlooked, but essential, prerequisite to the experiment design stage. The application of structural identifiability analysis to models of myelosuppression is used to demonstrate the importance of its considerations. It is shown that, under certain assumptions, these models are structurally identifiable and so drug and system specific parameters can truly be separated. Further it is shown via a meta-analysis of the literature that because of this the reported system parameter estimates for the “Friberg” or “Uppsala” model are consistent in the literatu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 2, 2018 Category: Drugs & Pharmacology Source Type: research

A distributed delay approach for modeling delayed outcomes in pharmacokinetics and pharmacodynamics studies
AbstractA distributed delay approach was proposed in this paper to model delayed outcomes in pharmacokinetics and pharmacodynamics studies. This approach was shown to be general enough to incorporate a wide array of pharmacokinetic and pharmacodynamic models as special cases including transit compartment models, effect compartment models, typical absorption models (either zero-order or first-order absorption), and a number of atypical (or irregular) absorption models (e.g., parallel first-order, mixed first-order and zero-order, inverse Gaussian, and Weibull absorption models). Real-life examples were given to demonstrate ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 24, 2018 Category: Drugs & Pharmacology Source Type: research

Leveraging model-informed approaches for drug discovery and development in the cardiovascular space
AbstractCardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, wheth...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 20, 2018 Category: Drugs & Pharmacology Source Type: research

Correction to: Scientific white paper on concentration-QTc modeling
AbstractThe original version of this article unfortunately contained an error in Equation  1 under the section “Pre-specified linear mixed effects model”. The correct equation has given below. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 12, 2018 Category: Drugs & Pharmacology Source Type: research

Delayed logistic indirect response models: realization of oscillating behavior
AbstractIndirect response (IDR) models are probably the most frequently applied tools relating the effect of a signal to a baseline response. A response modeled by such a classical IDR model will always return monotonously to its baseline after drug administration. We extend IDR models with a delay process, i.e. a retarded response state, that leads to oscillating response behavior. First, IDR models with a first-order production and second-order loss term based on the famous logistic equation are constructed. Second, a delay process similar to the delayed logistic equation is included. Relations of the classical IDR model...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 8, 2018 Category: Drugs & Pharmacology Source Type: research

Boolean network modeling in systems pharmacology
AbstractQuantitative systems pharmacology (QSP) is an emerging discipline that aims to discover how drugs modulate the dynamics of biological components in molecular and cellular networks and the impact of those perturbations on human pathophysiology. The integration of systems-based experimental and computational approaches is required to facilitate the advancement of this field. QSP models typically consist of a series of ordinary differential equations (ODE). However, this mathematical framework requires extensive knowledge of parameters pertaining to biological processes, which is often unavailable. An alternative fram...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 6, 2018 Category: Drugs & Pharmacology Source Type: research

gPKPDSim: a SimBiology ® -based GUI application for PKPD modeling in drug development
AbstractModeling and simulation (M&S) is increasingly used in drug development to characterize pharmacokinetic-pharmacodynamic (PKPD) relationships and support various efforts such as target feasibility assessment, molecule selection, human PK projection, and preclinical and clinical dose and schedule determination. While model development typically require mathematical modeling expertise, model exploration and simulations could in many cases be performed by scientists in various disciplines to support the design, analysis and interpretation of experimental studies. To this end, we have developed a versatile graphical ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 4, 2018 Category: Drugs & Pharmacology Source Type: research

Special issue: mathematical pharmacology
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 3, 2018 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics of dexmedetomidine during analgosedation in ICU patients
This study was performed in the group of 17 males and 10 females patients with a median age of 59.5  years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weig ht, patients’ health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typica...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 30, 2017 Category: Drugs & Pharmacology Source Type: research

Understanding and reducing complex systems pharmacology models based on a novel input –response index
AbstractA growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input –response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input–output relationship and allows to reduce t he dynamics to i...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 14, 2017 Category: Drugs & Pharmacology Source Type: research

Transit and lifespan in neutrophil production: implications for drug intervention
AbstractA comparison of the transit compartment ordinary differential equation modelling approach to distributed and discrete delay differential equation models is studied by focusing on Quartino ’s extension to the Friberg transit compartment model of myelosuppression, widely relied upon in the pharmaceutical sciences to predict the neutrophil response after chemotherapy, and on a QSP delay differential equation model of granulopoiesis. An extension to the Quartino model is provided by co nsidering a general number of transit compartments and introducing an extra parameter that allows for the decoupling of the matur...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 13, 2017 Category: Drugs & Pharmacology Source Type: research

A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim
AbstractProteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc recep...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 12, 2017 Category: Drugs & Pharmacology Source Type: research

Scientific white paper on concentration-QTc modeling
AbstractThe International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 5, 2017 Category: Drugs & Pharmacology Source Type: research

Lack of ethnic differences of moxifloxacin and metabolite pharmacokinetics in East Asian men
This study was designed to investigate ethnic differences in the pharmacokinetics (PKs) of moxifloxacin and its metabolites, M1 (sulfo conjugate) and M2 (acyl-glucuronate), among Japanese, Chinese, and Korean populations, following oral administration. We used a population PK modeling approach using data from a clinical study involving 79 healthy male volunteers. A comprehensive population PK model considering the PK mechanism of moxifloxacin and its metabolites was newly built. The structures of the final model were two-compartment for moxifloxacin and one-compartment for M1 and M2, with first-order absorption with lag ti...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 23, 2017 Category: Drugs & Pharmacology Source Type: research

Modeling energy intake and body weight effects of a long-acting amylin analogue
AbstractThe inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats. EI and body weight (BW) were measured daily and LAMY concentrations in plasma were assessed using defined time points following subcutaneous administration of the LAMY at different...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 23, 2017 Category: Drugs & Pharmacology Source Type: research

Population in vitro –in vivo pharmacokinetic model of first-pass metabolism: itraconazole and hydroxy-itraconazole
AbstractThe aim of this study was to develop a population in vitro –in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development. Model development was conducted in NONMEM in a stepwise manner. First, a model of i...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 17, 2017 Category: Drugs & Pharmacology Source Type: research

Comparison of tenofovir plasma and tissue exposure using a population pharmacokinetic model and bootstrap: a simulation study from observed data
AbstractSparse tissue sampling with intensive plasma sampling creates a unique data analysis problem in determining drug exposure in clinically relevant tissues. Tissue exposure may govern drug efficacy, as many drugs exert their actions in tissues. We compared tissue area-under-the-curve (AUC) generated from bootstrapped noncompartmental analysis (NCA) methods and compartmental nonlinear mixed effect (NLME) modeling. A model of observed data after single-dose tenofovir disoproxil fumarate was used to simulate plasma and tissue concentrations for two destructive tissue sampling schemes. Two groups of 100 data sets with den...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 8, 2017 Category: Drugs & Pharmacology Source Type: research

Model selection and averaging of nonlinear mixed-effect models for robust phase III dose selection
AbstractPopulation model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose –response shape functions, and then combine or select those candidate models are introduced. The key hypothesis is that by combining both model struc...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 4, 2017 Category: Drugs & Pharmacology Source Type: research

PKPD modeling of acquired resistance to anti-cancer drug treatment
AbstractNon-small cell lung cancer (NSCLC) patients greatly benefit from the treatment with tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, emergence of acquired resistance inevitable occurs after long-term treatment in most patients and limits clinical improvement. In the present study, resistance to drug treatment in patient-derived NSCLC xenograft mice was assessed and modeling and simulation was applied to understand the dynamics of drug resistance as a basis to explore more beneficial drug regimen. Two semi-mechanistic models were fitted to tumor growth inhibition prof...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 31, 2017 Category: Drugs & Pharmacology Source Type: research

A model of fracture risk used to examine the link between bone mineral density and the impact of different therapeutic mechanisms on fracture outcomes in patients with osteoporosis
AbstractA hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005 –2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The se arch resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56.75 years of study. The ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 28, 2017 Category: Drugs & Pharmacology Source Type: research

Assessing robustness of designs for random effects parameters for nonlinear mixed-effects models
AbstractOptimal designs for nonlinear models are dependent on the choice of parameter values. Various methods have been proposed to provide designs that are robust to uncertainty in the prior choice of parameter values. These methods are generally based on estimating the expectation of the determinant (or a transformation of the determinant) of the information matrix over the prior distribution of the parameter values. For high dimensional models this can be computationally challenging. For nonlinear mixed-effects models the question arises as to the importance of accounting for uncertainty in the prior value of the varian...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 24, 2017 Category: Drugs & Pharmacology Source Type: research

Evaluation and calibration of high-throughput predictions of chemical distribution to tissues
AbstractToxicokinetics (TK) provides critical information for integrating chemical toxicity and exposure assessments in order to determine potential chemical risk (i.e., the margin between toxic doses and plausible exposures). For thousands of chemicals that are present in our environment, in vivo TK data are lacking. The publicly available R package “httk” (version 1.8, named for “high throughput TK”) draws from a database of in vitro data and physico-chemical properties in order to run physiologically-based TK (PBTK) models for 553 compounds. The PBTK model parameters include tissue:plasma partiti...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 14, 2017 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1
The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C  >  T, 2677G >  T/A, and 3435C >  T) ofABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800  mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Ga...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 10, 2017 Category: Drugs & Pharmacology Source Type: research

Fractional calculus in pharmacokinetics
This article introduces the readers to the theory of fractional pharmacokinetics and the research challenges that arise. After a short introduction to the concepts of fractional calculus, and the main applications that have appeared in literature up to date, we address two important aspects. First, numerical methods that allow us to simulate fractional order systems accurately and second, optimal control methodologies that can be used to design d osing regimens to individuals and populations. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 3, 2017 Category: Drugs & Pharmacology Source Type: research

The American Conference on Pharmacometrics 2017 (ACoP8)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 26, 2017 Category: Drugs & Pharmacology Source Type: research

Abstracts for American conference on pharmacometrics 2017 (ACoP8)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 26, 2017 Category: Drugs & Pharmacology Source Type: research

ACoP8 Program
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 26, 2017 Category: Drugs & Pharmacology Source Type: research

Obituary: Gerhard Levy
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 19, 2017 Category: Drugs & Pharmacology Source Type: research

Mathematical description of drug –target interactions: application to biologics that bind to targets with two binding sites
AbstractThe emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations. The model was shown to be remarkably successful, not only in describing the observed ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 16, 2017 Category: Drugs & Pharmacology Source Type: research

Platform model describing pharmacokinetic properties of vc-MMAE antibody –drug conjugates
AbstractAntibody –drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. Th e goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predict ions, b...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 16, 2017 Category: Drugs & Pharmacology Source Type: research

Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system
AbstractThe combination of photodynamic therapy (PDT) with anti-tumor agents is a complimentary strategy to treat local cancers. We developed a unique photosensitizer (PS)-conjugated paclitaxel (PTX) prodrug in which a PS is excited by near-infrared wavelength light to site-specifically release PTX while generating singlet oxygen (SO) to effectively kill cancer cells with both PTX and SO. The aim of the present study was to identify the determinants influencing the combined efficacy of this light-activatable prodrug, especially the bystander killing effects from released PTX. Using PS-conjugated PTX as a model system, we d...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2017 Category: Drugs & Pharmacology Source Type: research

An automated sampling importance resampling procedure for estimating parameter uncertainty
In conclusion, the automated SIR procedure was successfully applied over a large variety of cases, and its user-friendly implementation in the PsN program enables an efficient estimation of parameter uncertainty in NLMEM. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 8, 2017 Category: Drugs & Pharmacology Source Type: research

Impact of mathematical pharmacology on practice and theory: four case studies
AbstractDrug-discovery has become a complex discipline in which the amount of knowledge about human biology, physiology, and biochemistry have increased. In order to harness this complex body of knowledge mathematics can play a critical role, and has actually already been doing so. We demonstrate through four case studies, taken from previously published data and analyses, what we can gain from mathematical/analytical techniques when nonlinear concentration-time courses have to be transformed into their equilibrium concentration-response (target or complex) relationships and new structures of drug potency have to be deciph...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 7, 2017 Category: Drugs & Pharmacology Source Type: research

Chemotherapeutic dosing implicated by pharmacodynamic modeling of in vitro cytotoxic data: a case study of paclitaxel
AbstractConventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights t...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 31, 2017 Category: Drugs & Pharmacology Source Type: research

Pharmacometrics models with hidden Markovian dynamics
AbstractThe aim of this paper is to provide an overview of pharmacometric models that involve some latent process with Markovian dynamics. Such models include hidden Markov models which may be useful for describing the dynamics of a disease state that jumps from one state to another at discrete times. On the contrary, diffusion models are continuous-time and continuous-state Markov models that are relevant for modelling non observed phenomena that fluctuate continuously and randomly over time. We show that an extension of these models to mixed effects models is straightforward in a population context. We then show how the ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 31, 2017 Category: Drugs & Pharmacology Source Type: research

Evaluation of pharmacokinetic model designs for subcutaneous infusion of insulin aspart
AbstractEffective mathematical modelling of continuous subcutaneous infusion pharmacokinetics should aid understanding and control in insulin therapy. Thorough analysis of candidate model performance is important for selecting the appropriate models. Eight candidate models for insulin pharmacokinetics included a range of modelled behaviours, parameters and complexity. The models were compared using clinical data from subjects with type 1 diabetes with continuous subcutaneous insulin infusion. Performance of the models was compared through several analyses: R2 for goodness of fit; the Akaike Information Criterion; a bootstr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 22, 2017 Category: Drugs & Pharmacology Source Type: research