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 18, 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 15, 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 10, 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 4, 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 - March 1, 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 21, 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 18, 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 15, 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 13, 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 13, 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 8, 2017 Category: Drugs & Pharmacology Source Type: research

What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles
AbstractThere are some 43 small molecules in the antibiotic development pipeline from late preclinical stage (7 compounds) through Phase 1 (11 molecules), Phase 2 (13 molecules) to Phase 3 (12 molecules). The majority of these are representatives of established antibiotic classes that have been modified to address problems of resistance. In addition, there is considerable activity around the discovery of novel classes of β-lactamase inhibitors with 10 combinations representing 4 inhibitor classes, at different stages of development. The combination of such inhibitors, which have broad activity against serine β-la...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 4, 2017 Category: Drugs & Pharmacology Source Type: research

Empirical models for fitting of oral concentration time curves with and without an intravenous reference
AbstractAppropriate model selection is important in fitting oral concentration –time data due to the complex character of the absorption process. When IV reference data are available, the problem is the selection of an empirical input function (absorption model). In the present examples a weighted sum of inverse Gaussian density functions (IG) was found most useful. It is sh own that alternative models (gamma and Weibull density) are only valid if the input function is log-concave. Furthermore, it is demonstrated for the first time that the sum of IGs model can be also applied to fit oral data directly (without IV da...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 1, 2017 Category: Drugs & Pharmacology Source Type: research

Adjusted adaptive Lasso for covariate model-building in nonlinear mixed-effect pharmacokinetic models
AbstractOne important aim in population pharmacokinetics (PK) and pharmacodynamics is identification and quantification of the relationships between the parameters and covariates. Lasso has been suggested as a technique for simultaneous estimation and covariate selection. In linear regression, it has been shown that Lasso possesses no oracle properties, which means it asymptotically performs as though the true underlying model was given in advance. Adaptive Lasso (ALasso) with appropriate initial weights is claimed to possess oracle properties; however, it can lead to poor predictive performance when there is multicollinea...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 31, 2017 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics and pharmacodynamics of IONIS-GCGR Rx , an antisense oligonucleotide for type 2 diabetes mellitus: a red blood cell lifespan model
The objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-GCGRRx via population-based modeling. The observed data were obtained from a Phase 1 (50, 100, 200, 300 and 400  mg) single- and multiple-dose study in healthy volunteers and a Phase 2 (100 and 200 mg) multiple-dose study in T2DM patients. The PK of IONIS GCGRRx was characterized by two primary systemic compartments and three absorption transit compartments with elimination out of the peripheral compartment. The fasting plasma glucose (FPG) PD was an indirect-response model (inhibition of FPG production) linke...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 28, 2017 Category: Drugs & Pharmacology Source Type: research

Target mediated drug disposition with drug –drug interaction, Part II: competitive and uncompetitive cases
We present competitive and uncompetitive drug –drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equati...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 10, 2017 Category: Drugs & Pharmacology Source Type: research

Target-mediated drug disposition with drug –drug interaction, Part I: single drug case in alternative formulations
AbstractTarget-mediated drug disposition (TMDD) describes drug binding with high affinity to a target such as a receptor. In application TMDD models are often over-parameterized and quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are essential to reduce the number of parameters. However, implementation of such approximations becomes difficult for TMDD models with drug –drug interaction (DDI) mechanisms. Hence, alternative but equivalent formulations are necessary for QE or QSS approximations. To introduce and develop such formulations, the single drug case is reanalyzed. This work opens the route fo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 10, 2017 Category: Drugs & Pharmacology Source Type: research

Drug disposition model of radiolabeled etelcalcetide in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis
AbstractEtelcalcetide (AMG 416) is an allosteric activator of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. To characterize the time course of etelcalcetide in different matrices (plasma, dialysate, urine, and feces), a drug disposition model was developed. Nonlinear mixed-effect modeling was used to describe data from six adults with CKD on hemodialysis who received a single intravenous dose of [14C]etelcalcetide (10  mg; 710 nCi) after hemodialysis (study NCT02054572). A three-compartment model with the following attributes ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 6, 2017 Category: Drugs & Pharmacology Source Type: research

Impact of saturable distribution in compartmental PK models: dynamics and practical use
AbstractWe explore the impact of saturable distribution over the central and the peripheral compartment in pharmacokinetic models, whilst assuming that back flow into the central compartiment is linear. Using simulations and analytical methods we demonstrate characteristic tell-tale differences in plasma concentration profiles of saturable versus linear distribution models, which can serve as a guide to their practical applicability. For two extreme cases, relating to (i) the size of the peripheral compartment with respect to the central compartment and (ii) the magnitude of the back flow as related to direct elimination f...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 3, 2017 Category: Drugs & Pharmacology Source Type: research

Experiment design for nonparametric models based on minimizing Bayes Risk: application to voriconazole $$^{1}$$ 1
AbstractAn experimental design approach is presented for individualized therapy in the special case where the prior information is specified by a nonparametric (NP) population model. Here, a NP model refers to a discrete probability model characterized by a finite set of support points and their associated weights. An important question arises as to how to best design experiments for this type of model. Many experimental design methods are based on Fisher information or other approaches originally developed for parametric models. While such approaches have been used with some success across various applications, it is inte...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 1, 2016 Category: Drugs & Pharmacology Source Type: research

The effect of Fisher information matrix approximation methods in population optimal design calculations
AbstractWith the increasing popularity of optimal design in drug development it is important to understand how the approximations and implementations of the Fisher information matrix (FIM) affect the resulting optimal designs. The aim of this work was to investigate the impact on design performance when using two common approximations to the population model and the full or block-diagonal FIM implementations for optimization of sampling points. Sampling schedules for two example experiments based on population models were optimized using the FO and FOCE approximations and the full and block-diagonal FIM implementations. Th...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 1, 2016 Category: Drugs & Pharmacology Source Type: research

Array of translational systems pharmacodynamic models of anti-cancer drugs
AbstractCancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti-cancer compounds is equally challenging, partly based on the complexity of biological and pharm...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 22, 2016 Category: Drugs & Pharmacology Source Type: research

Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling
AbstractTaking parameter uncertainty into account is key to make drug development decisions such as testing whether trial endpoints meet defined criteria. Currently used methods for assessing parameter uncertainty in NLMEM have limitations, and there is a lack of diagnostics for when these limitations occur. In this work, a method based on sampling importance resampling (SIR) is proposed, which has the advantage of being free of distributional assumptions and does not require repeated parameter estimation. To perform SIR, a high number of parameter vectors are simulated from a given proposal uncertainty distribution. Their...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 11, 2016 Category: Drugs & Pharmacology Source Type: research

dOFV distributions: a new diagnostic for the adequacy of parameter uncertainty in nonlinear mixed-effects models applied to the bootstrap
AbstractKnowledge of the uncertainty in model parameters is essential for decision-making in drug development. Contrarily to other aspects of nonlinear mixed effects models (NLMEM), scrutiny towards assumptions around parameter uncertainty is low, and no diagnostic exists to judge whether the estimated uncertainty is appropriate. This work aims at introducing a diagnostic capable of assessing the appropriateness of a given parameter uncertainty distribution. The new diagnostic was applied to case bootstrap examples in order to investigate for which dataset sizes case bootstrap is appropriate for NLMEM. The proposed diagnos...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 11, 2016 Category: Drugs & Pharmacology Source Type: research

Abstracts accepted for American Conference on Pharmacometrics 2016 (ACoP7)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2016 Category: Drugs & Pharmacology Source Type: research

Program (ACoP7)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2016 Category: Drugs & Pharmacology Source Type: research

The American Conference on Pharmacometrics 2016 (ACoP7)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2016 Category: Drugs & Pharmacology Source Type: research

Quantifying the therapeutic requirements and potential for combination therapy to prevent bacterial coinfection during influenza
AbstractSecondary bacterial infections (SBIs) exacerbate influenza-associated disease and mortality. Antimicrobial agents can reduce the severity of SBIs, but many have limited efficacy or cause adverse effects. Thus, new treatment strategies are needed. Kinetic models describing the infection process can help determine optimal therapeutic targets, the time scale on which a drug will be most effective, and how infection dynamics will change under therapy. To understand how different therapies perturb the dynamics of influenza infection and bacterial coinfection and to quantify the benefit of increasing a drug ’s effi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 27, 2016 Category: Drugs & Pharmacology Source Type: research

Quantitative characterization of in vitro bystander effect of antibody-drug conjugates
AbstractAntibody –drug conjugates (ADCs) are designed to target antigen expressing (Ag+) cells in a tumor. Once processed by the Ag+ cells, ADCs can release cytotoxic drug molecules that can diffuse out of Ag+ cells into the neighboring antigen-negative (Ag−) cells to induce their cytotoxicity. This additional efficacy of ADCs on Ag− cells in the presence of Ag+ cells is known as the ‘bystander effect’. Although the importance of this phenomena is widely acknowledged for effective killing of a heterogeneous tumor, the rate and extent of the bystander killing in a heterogeneous s...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 26, 2016 Category: Drugs & Pharmacology Source Type: research