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 25, 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 25, 2017 Category: Drugs & Pharmacology Source Type: research

ACoP8 Program
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 25, 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

Landmark and longitudinal exposure –response analyses in drug development
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 20, 2017 Category: Drugs & Pharmacology Source Type: research

Target-mediated drug disposition model for drugs with two binding sites that bind to a target with one binding site
AbstractThe paper extended the TMDD model to drugs with two identical binding sites (2-1 TMDD). The quasi-steady-state (2-1 QSS), quasi-equilibrium (2-1 QE), irreversible binding (2-1 IB), and Michaelis –Menten (2-1 MM) approximations of the model were derived. Using simulations, the 2-1 QSS approximation was compared with the full 2-1 TMDD model. As expected and similarly to the standard TMDD for monoclonal antibodies (mAb), 2-1 QSS predictions were nearly identical to 2-1 TMDD predictions, exce pt for times of fast changes following initiation of dosing, when equilibrium has not yet been reached. To illustrate prop...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 19, 2017 Category: Drugs & Pharmacology Source Type: research

Integrated TK –TD modeling for drug-induced concurrent tachycardia and QT changes in beagle dogs
This study also suggests that the TK–TD model can be used to iden tify direct drug effects on the non-rate-dependent QT component by dissociating QT changes from tachycardia and deriving a new QT correction method. The integrated TK–TD model presented here may serve as a novel quantitative framework for evaluating drug-induced concurrent changes in heart rate an d QT to potentially facilitate preclinical and clinical safety studies. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 22, 2017 Category: Drugs & Pharmacology Source Type: research

Improvement in latent variable indirect response modeling of multiple categorical clinical endpoints: application to modeling of guselkumab treatment effects in psoriatic patients
AbstractExposure –response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure–response of guselkumab, a human IgG1 monoclonal antibody in clini...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 20, 2017 Category: Drugs & Pharmacology Source Type: research

Challenges in longitudinal exposure-response modeling of data from complex study designs: a case study of modeling CDAI score for ustekinumab in patients with Crohn ’s disease
AbstractInformative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn ’s disease, where a commonly used composite endpoint Crohn’s Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and othe r response driven dose...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 16, 2017 Category: Drugs & Pharmacology Source Type: research

Deterministic identifiability of population pharmacokinetic and pharmacokinetic –pharmacodynamic models
AbstractIdentifiability is an important component of pharmacokinetic –pharmacodynamic (PKPD) model development. Structural identifiability is concerned with the uniqueness of the model parameters for a set of perfect input–output data and deterministic identifiability with the precision of parameter estimation given imperfect input–output data. We introduce two subcategories of deterministic identifiability, external and internal, and consider factors that distinguish between these forms. We define external deterministic identifiability as a function of externally controllable variables, i.e., the design,...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 13, 2017 Category: Drugs & Pharmacology Source Type: research

Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response
AbstractPembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 1, 2017 Category: Drugs & Pharmacology Source Type: research

Exploring inductive linearization for pharmacokinetic –pharmacodynamic systems of nonlinear ordinary differential equations
AbstractPharmacokinetic –pharmacodynamic systems are often expressed with nonlinear ordinary differential equations (ODEs). While there are numerous methods to solve such ODEs these methods generally rely on time-stepping solutions (e.g. Runge–Kutta) which need to be matched to the characteristics of the problem at han d. The primary aim of this study was to explore the performance of an inductive approximation which iteratively converts nonlinear ODEs to linear time-varying systems which can then be solved algebraically or numerically. The inductive approximation is applied to three examples, a simple nonlinea...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 26, 2017 Category: Drugs & Pharmacology Source Type: research

A two-step deconvolution-analysis-informed population pharmacodynamic modeling approach for drugs targeting pulsatile endogenous compounds
AbstractPharmacodynamic modeling of pulsatile endogenous compounds (e.g. growth hormone [GH]) is currently limited to the identification of a low number of pulses. Commonly used pharmacodynamic models are not able to capture the complexity of pulsatile secretion and therefore non-compartmental analyses are performed to extract summary statistics (mean, AUC, Cmax). The aim of this study was to develop a new quantification method that deals with highly variable pulsatile data by using a deconvolution-analysis-informed population pharmacodynamic modeling approach. Pulse frequency and pulse times were obtained by deconvolution...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 11, 2017 Category: Drugs & Pharmacology Source Type: research

Model-based meta-analysis for comparing Vitamin D2 and D3 parent-metabolite pharmacokinetics
AbstractAssociation of Vitamin D (D3& D2) and its 25OHD metabolite (25OHD3& 25OHD2) exposures with various diseases is an active research area. D3 and D2 dose-equivalency and each form ’s ability to raise 25OHD concentrations are not well-defined. The current work describes a population pharmacokinetic (PK) model for D2 and 25OHD2 and the use of a previously developed D3-25OHD3 PK model [1] for comparing D3 and D2-related exposures. Public-source D2 and 25OHD2 PK data in healthy or osteoporotic populations, including 17 studies representing 278 individuals (15 individual-level and 18 arm-level units), were se...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 2, 2017 Category: Drugs & Pharmacology Source Type: research

Impact of altered endogenous IgG on unspecific mAb clearance
AbstractImmunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data. We used a PBPK modelling approach to elucidate the influ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 24, 2017 Category: Drugs & Pharmacology Source Type: research

Estimation of QT interval prolongation through model-averaging
AbstractThe current method to analyze concentration-QT interval data, which is based on predictions conditional on a best model, fails to take into account the uncertainty of the model. Previous studies have suggested that failure to take into account model uncertainty using a best model approach can result in confidence intervals that are overly optimistic and may be too narrow. Theoretically, more realistic estimates are obtained using model-averaging where the overall point estimate and confidence interval are a weighted-average from a set of candidate models, the weights of which are equal to each model ’s Akaike...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 18, 2017 Category: Drugs & Pharmacology Source Type: research

Analysis of opioid consumption in clinical trials: a simulation based analysis of power of four approaches
This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE) model in NONMEM was used to simulate clinical trials of morphine consumption with and without a hypothetical adjuvant analgesic in doses equivalent to 15 –62% reduction in morphine consumption. Trials were simulated with duration of 24–96 h. Monte Carlo simulation and re-estimation were performed to determine sample size required to demonstrate efficacy with 80% power usingt test, Mann –Whitney rank sum test, time-to-event (TTE) modeling and RTTE modeling. Precision of efficacy es...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 7, 2017 Category: Drugs & Pharmacology Source Type: research

The effect of using a robust optimality criterion in model based adaptive optimization
AbstractOptimizing designs using robust (global) optimality criteria has been shown to be a more flexible approach compared to using local optimality criteria. Additionally, model based adaptive optimal design (MBAOD) may be less sensitive to misspecification in the prior information available at the design stage. In this work, we investigate the influence of using a local (lnD) or a robust (ELD) optimality criterion for a MBAOD of a simulated dose optimization study, for rich and sparse sampling schedules. A stopping criterion for accurate effect prediction is constructed to determine the endpoint of the MBAOD by minimizi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 6, 2017 Category: Drugs & Pharmacology Source Type: research

Age-structured population model of cell survival
AbstractAge-structured cell population model was introduced to describe cell survival. The impact of the environment on the cell population is represented by drug plasma concentration. A key model variable is the hazard of cell removal that is a subject to the environment effect. The model is capable of describing cohort and random labeling cell survival data. In addition, it accounts for cell loss due to labeling of cell sample, but it lacks ability to describe the effect of label elution on the survival data. The model was applied to red blood cell (RBC) survival data in two groups of Wistar rats obtained by two techniqu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 29, 2017 Category: Drugs & Pharmacology Source Type: research

PK –PD Compass: bringing infectious diseases pharmacometrics to the patient’s bedside
AbstractAntimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic –pharmacodynamic (PK–PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK–PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmaco kinetic (PK) and PK–PD data, patient-specific characteristi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 28, 2017 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic analysis of rebamipide in healthy Korean subjects with the characterization of atypical complex absorption kinetics
In this study, the population pharmacokinetic (PK) analysis of rebamipide (Reba) in healthy male Korean subjects was analyzed using the nonlinear mixed effects modeling method. The possible effects of physiological covariates and the multidrug resistance (MDR1) gene 3435C>T polymorphism on PK parameters were also investigated. Data were collected from a bioequivalence study, in which 26 subjects who participated in the study were administered a single oral dose of 100  mg Reba; only data from the reference formulation were used. Reba showed a relatively large inter-individual variability (from 2.6- to 3.3-fold) in ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 17, 2017 Category: Drugs & Pharmacology Source Type: research

Modeling and simulation in dose determination for biodefense products approved under the FDA animal rule
AbstractDevelopment of effective medical countermeasures for biodefense is vital to United States biopreparedness and response in the age of terrorism, both foreign and domestic. A traditional drug development pathway toward approval is not possible for most biodefense-related indications, creating the need for alternative development pathways such as the FDA ’s Animal Rule. Under this unique regulatory mechanism, FDA-approval is based on adequate and well-controlled animal studies when it is neither ethical nor feasible to conduct human efficacy studies. Translation of animal efficacy findings to humans is accomplis...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 14, 2017 Category: Drugs & Pharmacology Source Type: research

Editorial to the themed issue on focus on infectious disease
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 9, 2017 Category: Drugs & Pharmacology Source Type: research

Population PBPK modelling of trastuzumab: a framework for quantifying and predicting inter-individual variability
AbstractIn this work we proposed a population physiologically-based pharmacokinetic (popPBPK) framework for quantifying and predicting inter-individual pharmacokinetic variability using the anti-HER2 monoclonal antibody (mAb) trastuzumab as an example. First, a PBPK model was developed to account for the possible mechanistic sources of variability. Within the model, five key factors that contribute to variability were identified and the nature of their contribution was quantified with local and global sensitivity analyses. The five key factors were the concentration of membrane-bound HER2 (\(Ag\)), the convective flow rate...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 3, 2017 Category: Drugs & Pharmacology Source Type: research

Exposure –disease response analysis of natalizumab in subjects with multiple sclerosis
The objective of this analysis was to develop a population exposure –response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response. In the case of the Gd lesion count model, a bimodal model that distributed subjects into two subpopulations based on low or high baseline Gd lesion count...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 28, 2017 Category: Drugs & Pharmacology Source Type: research

Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments
AbstractNicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc –FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 20, 2017 Category: Drugs & Pharmacology Source Type: research

Exposure –response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults
In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 17, 2017 Category: Drugs & Pharmacology Source Type: research

The multistate tuberculosis pharmacometric model: a semi-mechanistic pharmacokinetic-pharmacodynamic model for studying drug effects in an acute tuberculosis mouse model
AbstractThe Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin onMycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected withM. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98  mg&mi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 14, 2017 Category: Drugs & Pharmacology Source Type: research

Comparison of non-compartmental and mixed effect modelling methods for establishing bioequivalence for the case of two compartment kinetics and censored concentrations
AbstractNon-compartmental analysis (NCA) is regarded as the standard for establishing bioequivalence, despite its limitations and the existence of alternative methods such as non-linear mixed effects modelling (NLMEM). Comparisons of NCA and NLMEM in bioequivalence testing have been limited to drugs with one-compartment kinetics and have included a large number of different approaches. A simulation tool was developed with the ability to rapidly compare NCA and NLMEM methods in determining bioequivalence using both R and NONMEM and applied to a drug with two-compartment pharmacokinetics. Concentration –time profiles w...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 12, 2017 Category: Drugs & Pharmacology Source Type: research

Nonlinear mixed-effects models for pharmacokinetic data analysis: assessment of the random-effects distribution
AbstractNonlinear mixed-effects models are frequently used for pharmacokinetic data analysis, and they account for inter-subject variability in pharmacokinetic parameters by incorporating subject-specific random effects into the model. The random effects are often assumed to follow a (multivariate) normal distribution. However, many articles have shown that misspecifying the random-effects distribution can introduce bias in the estimates of parameters and affect inferences about the random effects themselves, such as estimation of the inter-subject variability. Because random effects are unobservable latent variables, it i...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 12, 2017 Category: Drugs & Pharmacology Source Type: research

Prognostic value of galactomannan: current evidence for monitoring response to antifungal therapy in patients with invasive aspergillosis
AbstractGalactomannan (GM) is a polysaccharide present in the cell wall ofAspergillus spp. that is released during growth of the organism. It has been successfully used to aide in the diagnosis of invasive aspergillosis allowing for earlier recognition of disease compared to conventional methods. Since its implementation in the clinic as a diagnostic tool, GM has been used in experimental models to measure therapeutic response. Several clinical studies describe the prognostic value of GM. Herein, we review the evidence supporting the utilization of GM antigen as a biomarker to measure response to systemic antifungal therap...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 7, 2017 Category: Drugs & Pharmacology Source Type: research