744 results match your criteria Journal of Pharmacokinetics and Pharmacodynamics[Journal]


Reproducible pharmacokinetics.

J Pharmacokinet Pharmacodyn 2019 Apr 19. Epub 2019 Apr 19.

Departments of Medicine, Health Research and Policy, Biomedical Data Science, and Statistics, Stanford Prevention Research Center, Meta-Research Innovation Center at Stanford (METRICS), Stanford University, 1265 Welch Road, Medical School Office Building Room X306, Stanford, CA, 94305, USA.

Reproducibility is a highly desired feature of scientific investigation in general, and it has special connotations for research in pharmacokinetics, a vibrant field with over 500,000 publications to-date. It is important to be able to differentiate between genuine heterogeneity in pharmacokinetic parameters from heterogeneity that is due to errors and biases. This overview discusses efforts and opportunities to diminish the latter type of undesirable heterogeneity. Read More

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http://dx.doi.org/10.1007/s10928-019-09621-yDOI Listing

Development of visual predictive checks accounting for multimodal parameter distributions in mixture models.

J Pharmacokinet Pharmacodyn 2019 Apr 9. Epub 2019 Apr 9.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

The assumption of interindividual variability being unimodally distributed in nonlinear mixed effects models does not hold when the population under study displays multimodal parameter distributions. Mixture models allow the identification of parameters characteristic to a subpopulation by describing these multimodalities. Visual predictive check (VPC) is a standard simulation based diagnostic tool, but not yet adapted to account for multimodal parameter distributions. Read More

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http://dx.doi.org/10.1007/s10928-019-09632-9DOI Listing

Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis.

J Pharmacokinet Pharmacodyn 2019 Apr 8. Epub 2019 Apr 8.

Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.

This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0-0. Read More

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http://dx.doi.org/10.1007/s10928-019-09633-8DOI Listing
April 2019
1 Read

Population pharmacokinetic reanalysis of a Diazepam PBPK model: a comparison of Stan and GNU MCSim.

J Pharmacokinet Pharmacodyn 2019 Apr 4. Epub 2019 Apr 4.

School of Chemical Engineering, National Technical University of Athens, 9 Heroon Polytechneiou Street, Zografou Campus, 15780, Athens, Greece.

The aim of this study is to benchmark two Bayesian software tools, namely Stan and GNU MCSim, that use different Markov chain Monte Carlo (MCMC) methods for the estimation of physiologically based pharmacokinetic (PBPK) model parameters. The software tools were applied and compared on the problem of updating the parameters of a Diazepam PBPK model, using time-concentration human data. Both tools produced very good fits at the individual and population levels, despite the fact that GNU MCSim is not able to consider multivariate distributions. Read More

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http://dx.doi.org/10.1007/s10928-019-09630-xDOI Listing
April 2019
1 Read

Estimating parameters of nonlinear dynamic systems in pharmacology using chaos synchronization and grid search.

J Pharmacokinet Pharmacodyn 2019 Mar 30. Epub 2019 Mar 30.

Freedman Patent, Harleysville, PA, 19438, USA.

Bridging fundamental approaches to model optimization for pharmacometricians, systems pharmacologists and statisticians is a critical issue. These fields rely primarily on Maximum Likelihood and Extended Least Squares metrics with iterative estimation of parameters. Our research combines adaptive chaos synchronization and grid search to estimate physiological and pharmacological systems with emergent properties by exploring deterministic methods that are more appropriate and have potentially superior performance than classical numerical approaches, which minimize the sum of squares or maximize the likelihood. Read More

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http://dx.doi.org/10.1007/s10928-019-09629-4DOI Listing
March 2019
1 Read

Preface to Special Issue for Panos Macheras.

Authors:
Robert R Bies

J Pharmacokinet Pharmacodyn 2019 Mar 30. Epub 2019 Mar 30.

University at Buffalo - The State University of New York, Buffalo, NY, USA.

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http://dx.doi.org/10.1007/s10928-019-09631-wDOI Listing

Panos Macheras: a pioneering scientist in pharmaceutical science.

J Pharmacokinet Pharmacodyn 2019 Mar 28. Epub 2019 Mar 28.

School of Pharmacy and Pharmaceutical Sciences, Computational and Data Enabled Science and Engineering Program, State University of New York at Buffalo, Buffalo, NY, USA.

Professor Panos Macheras is a pioneering scientist in pharmacokinetics, pharmacodynamics and biopharmaceutics. His many important contributions to pharmaceutical science are reviewed. Read More

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http://dx.doi.org/10.1007/s10928-019-09628-5DOI Listing

Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs.

J Pharmacokinet Pharmacodyn 2019 Mar 25. Epub 2019 Mar 25.

Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, 94143-0912, USA.

Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration-time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-life. This simplified disposition model at steady-state allows comparisons of measurable parameters (i. Read More

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http://link.springer.com/10.1007/s10928-019-09626-7
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http://dx.doi.org/10.1007/s10928-019-09626-7DOI Listing
March 2019
5 Reads

Accounting for inter-correlation between enzyme abundance: a simulation study to assess implications on global sensitivity analysis within physiologically-based pharmacokinetics.

J Pharmacokinet Pharmacodyn 2019 Mar 23. Epub 2019 Mar 23.

Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.

Physiologically based pharmacokinetic (PBPK) models often include several sets of correlated parameters, such as organ volumes and blood flows. Because of recent advances in proteomics, it has been demonstrated that correlations are also present between abundances of drug-metabolising enzymes in the liver. As the focus of population PBPK has shifted the emphasis from the average individual to theoretically conceivable extremes, reliable estimation of the extreme cases has become paramount. Read More

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http://dx.doi.org/10.1007/s10928-019-09627-6DOI Listing

Structural identifiability and sensitivity.

J Pharmacokinet Pharmacodyn 2019 Mar 20. Epub 2019 Mar 20.

Faculty of Pharmacy, SMARTc - CRCM - INSERM UMR1068 - CNRS UMR7258 - AMU UM105, 27, bd. Jean Moulin, 13385, Marseille Cedex 5, France.

Ordinary differential equation models often contain a large number of parameters that must be determined from measurements by estimation procedure. For an estimation to be successful there must be a unique set of parameters that can have produced the measured data. This is not the case if a model is not structurally identifiable with the given set of inputs and outputs. Read More

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http://link.springer.com/10.1007/s10928-019-09624-9
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http://dx.doi.org/10.1007/s10928-019-09624-9DOI Listing
March 2019
3 Reads

Monte Carlo simulations in drug release.

J Pharmacokinet Pharmacodyn 2019 Mar 18. Epub 2019 Mar 18.

Division of Applied Mathematics, Department of Chemical Engineering, University of Patras, Patras, Greece.

We present methods based on simple sampling Monte Carlo simulations that are used in the study of controlled drug release from devices of various shapes and characteristics. The manuscript is part of a special tribute issue for Prof. Panos Macheras and we have chosen applications of the Monte Carlo method in the field of drug release that were pioneered by him and his research group. Read More

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http://dx.doi.org/10.1007/s10928-019-09625-8DOI Listing

Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma.

J Pharmacokinet Pharmacodyn 2019 Mar 11. Epub 2019 Mar 11.

Pfizer Oncology, Collegeville, PA, USA.

This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CL) term and identified potential covariates that may be important predictors of variability in InO distribution and elimination. This analysis was conducted by pooling data from 2 studies of single-agent InO in patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL), 3 studies of single-agent InO, 5 studies of InO plus rituximab (R-InO), and 1 study of R-InO plus chemotherapy in patients with R/R B-cell non-Hodgkin lymphoma (NHL). Pharmacokinetic data included 8361 InO concentration-time observations that were modeled using nonlinear mixed-effects analysis. Read More

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http://dx.doi.org/10.1007/s10928-018-9614-9DOI Listing
March 2019
1 Read

Bioequivalence for highly variable drugs: regulatory agreements, disagreements, and harmonization.

J Pharmacokinet Pharmacodyn 2019 Feb 23. Epub 2019 Feb 23.

Semmelweis University, Budapest, Hungary.

Regulatory authorities introduced procedures in the last decade for evaluating the bioequivalence (BE) for highly variable drugs. These approaches are similar in principle but differ in details. For example, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend differing regulatory constants. Read More

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http://dx.doi.org/10.1007/s10928-019-09623-wDOI Listing
February 2019
3 Reads

Challenge model of TNF turnover at varying LPS and drug provocations.

J Pharmacokinet Pharmacodyn 2019 Feb 18. Epub 2019 Feb 18.

Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7028, 75007, Uppsala, Sweden.

A mechanism-based biomarker model of TNF-response, including different external provocations of LPS challenge and test compound intervention, was developed. The model contained system properties (such as k, k), challenge characteristics (such as k, k, K, S, SC) and test-compound-related parameters (I, IC). The exposure to test compound was modelled by means of first-order input and Michaelis-Menten type of nonlinear elimination. Read More

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http://dx.doi.org/10.1007/s10928-019-09622-xDOI Listing
February 2019

Indirect pharmacodynamic models for responses with circadian removal.

J Pharmacokinet Pharmacodyn 2019 Feb 29;46(1):89-101. Epub 2019 Jan 29.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.

Rhythmicity in baseline responses over a 24-h period for an indirect pharmacological effect R(t) can arise from either a periodic time-dependent input rate [Formula: see text] or a periodic time-dependent loss constant [Formula: see text]. If either [Formula: see text] or [Formula: see text] follows some nonstationary biological rhythm (e.g. Read More

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http://dx.doi.org/10.1007/s10928-019-09620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447046PMC
February 2019
1 Read

Modelling of oscillatory cortisol response in horses using a Bayesian population approach for evaluation of dexamethasone suppression test protocols.

J Pharmacokinet Pharmacodyn 2019 Feb 23;46(1):75-87. Epub 2019 Jan 23.

Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden.

Cortisol is a steroid hormone relevant to immune function in horses and other species and shows a circadian rhythm. The glucocorticoid dexamethasone suppresses cortisol in horses. Pituitary pars intermedia dysfunction (PPID) is a disease in which the cortisol suppression mechanism through dexamethasone is challenged. Read More

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http://dx.doi.org/10.1007/s10928-018-09617-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394511PMC
February 2019

Population pharmacokinetic analysis of danvatirsen supporting flat dosing switch.

J Pharmacokinet Pharmacodyn 2019 Feb 19;46(1):65-74. Epub 2019 Jan 19.

Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.

Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. Read More

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http://link.springer.com/10.1007/s10928-019-09619-6
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http://dx.doi.org/10.1007/s10928-019-09619-6DOI Listing
February 2019
5 Reads

Ordinary differential equation approximation of gamma distributed delay model.

J Pharmacokinet Pharmacodyn 2019 Feb 7;46(1):53-63. Epub 2019 Jan 7.

Department of Pharmaceutical Sciences, University at Buffalo, 370 Kapoor Hall, Buffalo, NY, 14214, USA.

In many models of pharmacodynamic systems with delays, a delay of an input is introduced by means of the convolution with the gamma distribution. An approximation of the convolution integral of bound functions based on a system of ordinary differential equations that utilizes properties of the binomial series has been introduced. The approximation converges uniformly on every compact time interval and an estimate of the approximation error has been found [Formula: see text] where [Formula: see text] is the number of differential equations and [Formula: see text] is the shape parameter of the gamma distribution. Read More

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http://dx.doi.org/10.1007/s10928-018-09618-zDOI Listing
February 2019
1 Read

Application of new measures of nonlinearity to parameter estimation and simulations in individual pharmacokinetic analyses.

J Pharmacokinet Pharmacodyn 2019 Feb 3;46(1):43-52. Epub 2019 Jan 3.

Canisius College, Buffalo, NY, USA.

Since simulation studies are widely used in pharmacokinetics, it is necessary to ascertain their validity. An important, well-documented, concern that may negatively impact the validity of estimated parameters in pharmacokinetic models is existence of multiple minima of the criterion used in estimation. A presence of multiple minima causes instability of the estimates, dependence of the parameter estimates on the initial values, and bimodal (or, generally, multimodal) distributions of the estimated parameters. Read More

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http://dx.doi.org/10.1007/s10928-018-09616-1DOI Listing
February 2019
1 Read

Variance based global sensitivity analysis of physiologically based pharmacokinetic absorption models for BCS I-IV drugs.

J Pharmacokinet Pharmacodyn 2019 Feb 14;46(1):27-42. Epub 2018 Dec 14.

Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.

Regulatory agencies have a strong interest in sensitivity analysis for the evaluation of physiologically-based pharmacokinetic (PBPK) models used in pharmaceutical research and drug development and regulatory submissions. One of the applications of PBPK is the prediction of fraction absorbed and bioavailability for drugs following oral administration. In this context, we performed a variance based global sensitivity analysis (GSA) on in-house PBPK models for drug absorption, with the aim of identifying key parameters that influence the predictions of the fraction absorbed and the bioavailability for neutral, acidic and basic compounds. Read More

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http://dx.doi.org/10.1007/s10928-018-9615-8DOI Listing
February 2019
5 Reads

Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling.

J Pharmacokinet Pharmacodyn 2019 Feb 16;46(1):15-25. Epub 2018 Nov 16.

School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, Athens, GA, USA.

Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Read More

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http://link.springer.com/10.1007/s10928-018-9612-y
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http://dx.doi.org/10.1007/s10928-018-9612-yDOI Listing
February 2019
16 Reads

Development of a nonlinear hierarchical model to describe the disposition of deuterium in mother-infant pairs to assess exclusive breastfeeding practice.

J Pharmacokinet Pharmacodyn 2019 Feb 14;46(1):1-13. Epub 2018 Nov 14.

School of Pharmacy, University of Otago, Dunedin, New Zealand.

The World Health Organization recommends exclusive breastfeeding (EBF) for the first 6 months after birth. The deuterium oxide dose-to-the-mother (DTM) technique is used to distinguish EBF based on a cut-off (< 25 g/day) of water intake from sources other than breastmilk. This value is based on a theoretical threshold and has not been verified in field studies. Read More

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http://link.springer.com/10.1007/s10928-018-9613-x
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http://dx.doi.org/10.1007/s10928-018-9613-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394541PMC
February 2019
4 Reads

MPBPK-TMDD models for mAbs: alternative models, comparison, and identifiability issues.

J Pharmacokinet Pharmacodyn 2018 Dec 10;45(6):787-802. Epub 2018 Nov 10.

Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stockley Park, UK.

The aim of the present study was to evaluate model identifiability when minimal physiologically-based pharmacokinetic (mPBPK) models are integrated with target mediated drug disposition (TMDD) models in the tissue compartment. Three quasi-steady-state (QSS) approximations of TMDD dynamics were explored: on (a) antibody-target complex, (b) free target, and (c) free antibody concentrations in tissue. The effects of the QSS approximations were assessed via simulations, taking as reference the mPBPK-TMDD model with no simplifications. Read More

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http://link.springer.com/10.1007/s10928-018-9608-7
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http://dx.doi.org/10.1007/s10928-018-9608-7DOI Listing
December 2018
25 Reads

Modeling the acute effects of exercise on insulin kinetics in type 1 diabetes.

J Pharmacokinet Pharmacodyn 2018 Dec 3;45(6):829-845. Epub 2018 Nov 3.

Department of Mechanical Engineering, University of California Berkeley, Berkeley, CA, USA.

Our objective is to develop a physiology-based model of insulin kinetics to understand how exercise alters insulin concentrations in those with type 1 diabetes (T1D). We reveal the relationship between the insulin absorption rate ([Formula: see text]) from subcutaneous tissue, the insulin delivery rate ([Formula: see text]) to skeletal muscle, and two physiological parameters that characterize the tissue: the perfusion rate (Q) and the capillary permeability surface area (PS), both of which increase during exercise because of capillary recruitment. We compare model predictions to experimental observations from two pump-wearing T1D cohorts [resting subjects ([Formula: see text]) and exercising subjects ([Formula: see text])] who were each given a mixed-meal tolerance test and a bolus of insulin. Read More

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http://link.springer.com/10.1007/s10928-018-9611-z
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http://dx.doi.org/10.1007/s10928-018-9611-zDOI Listing
December 2018
27 Reads
1.460 Impact Factor

A pre-clinical quantitative model predicts the pharmacokinetics/pharmacodynamics of an anti-BDCA2 monoclonal antibody in humans.

J Pharmacokinet Pharmacodyn 2018 Dec 30;45(6):817-827. Epub 2018 Oct 30.

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.

BIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we utilized pre-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to develop a non-human primate (NHP) model and to address whether the NHP model can be successfully scaled to predict the human PK/PD. Read More

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http://link.springer.com/10.1007/s10928-018-9609-6
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http://dx.doi.org/10.1007/s10928-018-9609-6DOI Listing
December 2018
7 Reads

Modeling near-continuous clinical endpoint as categorical: application to longitudinal exposure-response modeling of Mayo scores for golimumab in patients with ulcerative colitis.

J Pharmacokinet Pharmacodyn 2018 Dec 30;45(6):803-816. Epub 2018 Oct 30.

Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 1400 McKean Road, Spring House, PA, 19477, USA.

Accurate characterization of exposure-response relationship of clinical endpoints is important in drug development to identify optimal dose regimens. Endpoints with ≥ 10 ordered categories are typically analyzed as continuous. This manuscript aims to show circumstances where it is advantageous to analyze such data as ordered categorical. Read More

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http://link.springer.com/10.1007/s10928-018-9610-0
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http://dx.doi.org/10.1007/s10928-018-9610-0DOI Listing
December 2018
4 Reads

The use of PBPK modeling across the pediatric age range using propofol as a case.

J Pharmacokinet Pharmacodyn 2018 Dec 8;45(6):765-785. Epub 2018 Oct 8.

Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.

The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. Read More

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http://link.springer.com/10.1007/s10928-018-9607-8
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http://dx.doi.org/10.1007/s10928-018-9607-8DOI Listing
December 2018
9 Reads

Extrapolation of praziquantel pharmacokinetics to a pediatric population: a cautionary tale.

J Pharmacokinet Pharmacodyn 2018 Oct 14;45(5):747-762. Epub 2018 Sep 14.

Swiss Tropical and Public Health Institute, Socinstr. 57, CH-4002, Basel, Switzerland.

L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. Read More

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http://dx.doi.org/10.1007/s10928-018-9601-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182730PMC
October 2018
11 Reads

Abstracts for the Ninth American Conference on Pharmacometrics (ACoP9).

Authors:

J Pharmacokinet Pharmacodyn 2018 Sep 10:3-134. Epub 2018 Sep 10.

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http://link.springer.com/10.1007/s10928-018-9606-9
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http://dx.doi.org/10.1007/s10928-018-9606-9DOI Listing
September 2018
4 Reads

The Ninth American Conference on Pharmacometrics (ACoP9).

Authors:

J Pharmacokinet Pharmacodyn 2018 Oct;45(Suppl 1)

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http://dx.doi.org/10.1007/s10928-018-9605-xDOI Listing
October 2018
1 Read

Correction to: Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models.

J Pharmacokinet Pharmacodyn 2018 Oct;45(5):763

Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC, Leiden, The Netherlands.

The original version of this article was published open access. Unfortunately, due to a technical issue, the copyright holder name in the online version (HTML and XML) is incorrectly published as "Springer Science+Business Media, LLC, part of Springer Nature 2018". Instead, it should be "The Author(s) 2018". Read More

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http://dx.doi.org/10.1007/s10928-018-9604-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182733PMC
October 2018
9 Reads

Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts.

J Pharmacokinet Pharmacodyn 2018 Oct 1;45(5):733-746. Epub 2018 Aug 1.

Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, USA.

The anticancer effects of combined gemcitabine and birinapant were demonstrated as synergistic in PANC-1 cells in vitro. In this study, pharmacokinetic information derived from experiments and the literature was utilized to develop full physiologically-based pharmacokinetic (PBPK) models that characterize individual drugs. The predicted intra-tumor drug concentrations were used as the driving force within a linked PBPK/PD model for treatment-mediated changes in tumor volume in a xenograft mouse model. Read More

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http://dx.doi.org/10.1007/s10928-018-9603-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160358PMC
October 2018
26 Reads

An item response theory based integrated model of headache, nausea, photophobia, and phonophobia in migraine patients.

J Pharmacokinet Pharmacodyn 2018 Oct 24;45(5):721-731. Epub 2018 Jul 24.

Department of Pharmacology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.

This study developed an integrated model of severity scores of migraine headache and the incidence of nausea, photophobia, and phonophobia to predict the natural time course of migraine symptoms, which are likely to occur by a common disease progression mechanism. Data were acquired from two phase 3 clinical trials conducted during the development of eletriptan. Only the placebo arm was used for analysis. Read More

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http://dx.doi.org/10.1007/s10928-018-9602-0DOI Listing
October 2018
1 Read

Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

J Pharmacokinet Pharmacodyn 2018 Oct 10;45(5):707-719. Epub 2018 Jul 10.

Oncology/Pharmacometrics, Novartis Pharmaceuticals Corporation, One Health Plaza, 337/A06/7E, East Hanover, NJ, 07936-1080, USA.

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. Read More

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http://dx.doi.org/10.1007/s10928-018-9600-2DOI Listing
October 2018
15 Reads

Mathematical analysis and drug exposure evaluation of pharmacokinetic models with endogenous production and simultaneous first-order and Michaelis-Menten elimination: the case of single dose.

J Pharmacokinet Pharmacodyn 2018 Oct 9;45(5):693-705. Epub 2018 Jul 9.

Faculté de pharmacie, Université de Montréal, Montréal, QC, H3C 3J7, Canada.

Drugs with an additional endogenous source often exhibit simultaneous first-order and Michaelis-Menten elimination and are becoming quite common in pharmacokinetic modeling. In this paper, we investigate the case of single dose intravenous bolus administration for the one-compartment model. Relying on a formerly introduced transcendent function, we were able to analytically express the concentration time course of this model and provide the pharmacokinetic interpretation of its components. Read More

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http://dx.doi.org/10.1007/s10928-018-9599-4DOI Listing
October 2018
2 Reads
1.460 Impact Factor

Joint longitudinal model development: application to exposure-response modeling of ACR and DAS scores in rheumatoid arthritis patients treated with sirukumab.

J Pharmacokinet Pharmacodyn 2018 Oct 30;45(5):679-691. Epub 2018 Jun 30.

Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 1400 McKean Road, Spring House, PA, 19477, USA.

Exposure-response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint 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 presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure-response modeling of sirukumab. Read More

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http://dx.doi.org/10.1007/s10928-018-9598-5DOI Listing
October 2018
21 Reads
1.460 Impact Factor

Modeling and simulations to support dose selection for eslicarbazepine acetate therapy in pediatric patients with partial-onset seizures.

J Pharmacokinet Pharmacodyn 2018 Aug 9;45(4):649-658. Epub 2018 Jun 9.

Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752, USA.

Modeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4-17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2-18 years of age treated with ESL 5-30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (including body weight and concomitant use of carbamazepine, levetiracetam, and phenobarbital-like antiepileptic drugs [AEDs]) on variability in PK parameters. Read More

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http://link.springer.com/10.1007/s10928-018-9596-7
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http://dx.doi.org/10.1007/s10928-018-9596-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061080PMC
August 2018
4 Reads

Reduced and optimized trial designs for drugs described by a target mediated drug disposition model.

J Pharmacokinet Pharmacodyn 2018 Aug 8;45(4):637-647. Epub 2018 Jun 8.

Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden.

Monoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e. Read More

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http://dx.doi.org/10.1007/s10928-018-9594-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061097PMC
August 2018
3 Reads

Physiologically based pharmacokinetic-quantitative systems toxicology and safety (PBPK-QSTS) modeling approach applied to predict the variability of amitriptyline pharmacokinetics and cardiac safety in populations and in individuals.

J Pharmacokinet Pharmacodyn 2018 Oct 25;45(5):663-677. Epub 2018 Jun 25.

Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688, Krakow, Poland.

The physiologically based pharmacokinetic (PBPK) models allow for predictive assessment of variability in population of interest. One of the future application of PBPK modeling is in the field of precision dosing and personalized medicine. The aim of the study was to develop PBPK model for amitriptyline given orally, predict the variability of cardiac concentrations of amitriptyline and its main metabolite-nortriptyline in populations as well as individuals, and simulate the influence of those xenobiotics in therapeutic and supratherapeutic concentrations on human electrophysiology. Read More

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http://dx.doi.org/10.1007/s10928-018-9597-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182726PMC
October 2018
8 Reads

Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models.

J Pharmacokinet Pharmacodyn 2018 Aug 18;45(4):621-635. Epub 2018 May 18.

Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC, Leiden, The Netherlands.

Drug-target binding kinetics (as determined by association and dissociation rate constants, k and k) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug-target binding model should be used in lieu of the effect compartment model. Read More

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http://dx.doi.org/10.1007/s10928-018-9593-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061075PMC
August 2018
9 Reads

A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation.

J Pharmacokinet Pharmacodyn 2018 Jun 7;45(3):365-381. Epub 2018 May 7.

Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. Read More

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http://dx.doi.org/10.1007/s10928-018-9589-6DOI Listing
June 2018
11 Reads

Population pharmacokinetics and exposure-response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia.

J Pharmacokinet Pharmacodyn 2018 Jun 7;45(3):505-522. Epub 2018 May 7.

Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, USA.

Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure-response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7-420 mg at various frequencies, either intravenously or subcutaneously. Read More

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http://dx.doi.org/10.1007/s10928-018-9592-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953983PMC
June 2018
9 Reads

Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma.

J Pharmacokinet Pharmacodyn 2018 Aug 3;45(4):607-620. Epub 2018 May 3.

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, 6550 Sanger Road, Office #469, Orlando, FL, 32827, USA.

Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature. Read More

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http://dx.doi.org/10.1007/s10928-018-9590-0DOI Listing
August 2018
2 Reads

Editorial to themed issue: Recent advances in cardiovascular pharmacokinetic-pharmacodynamic modeling and simulation.

Authors:
Peter Bonate

J Pharmacokinet Pharmacodyn 2018 Jun 2;45(3):353. Epub 2018 May 2.

Astellas, 1 Astellas Way, Northbrook, IL, 60062, USA.

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http://dx.doi.org/10.1007/s10928-018-9591-zDOI Listing
June 2018
6 Reads

Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver.

J Pharmacokinet Pharmacodyn 2018 Aug 27;45(4):557-575. Epub 2018 Apr 27.

Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.

A multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBPβ) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dynamics were evaluated. Read More

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http://dx.doi.org/10.1007/s10928-018-9585-xDOI Listing
August 2018
3 Reads

Projected 24-hour post-dose ocular itching scores post-treatment with olopatadine 0.7% versus 0.2.

J Pharmacokinet Pharmacodyn 2018 Aug 21;45(4):593-605. Epub 2018 Apr 21.

Alcon Laboratories, Inc., Fort Worth, TX, USA.

Olopatadine is an antihistamine and mast cell stabilizer used for treating allergic conjunctivitis. Olopatadine 0.7% has been recently approved for daily dosing in the US, which supersedes the previously approved 0. Read More

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http://dx.doi.org/10.1007/s10928-018-9588-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061088PMC
August 2018
4 Reads

Physiologically-based modeling and interspecies prediction of paclitaxel pharmacokinetics.

J Pharmacokinet Pharmacodyn 2018 Aug 18;45(4):577-592. Epub 2018 Apr 18.

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.

The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol-Taxol) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported paclitaxel plasma and tissue concentration-time data following single intravenous bolus administration of Taxol to mice were used; and the PBPK model included plasma, liver, lungs, kidneys, spleen, heart, gastrointestinal tract, and remainder compartments. The final model resulted in a good description of the experimental plasma and tissues data in mice, where all tissues were represented by a single compartment, except the remainder that included two sub-compartments. Read More

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http://dx.doi.org/10.1007/s10928-018-9586-9DOI Listing
August 2018
11 Reads

Importance of QT/RR hysteresis correction in studies of drug-induced QTc interval changes.

J Pharmacokinet Pharmacodyn 2018 Jun 12;45(3):491-503. Epub 2018 Apr 12.

Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

QT/RR hysteresis and QT/RR adaptation are interlinked but separate physiological processes signifying how quickly and how much QT interval changes when heart rate changes, respectively. While QT interval duration is, as a rule, corrected for heart rate in terms of the QT/RR adaptation, the correction for QT/RR hysteresis is frequently omitted in studies of drug-induced QTc changes. This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations. Read More

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http://dx.doi.org/10.1007/s10928-018-9587-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953973PMC
June 2018
7 Reads

Model reduction in mathematical pharmacology : Integration, reduction and linking of PBPK and systems biology models.

J Pharmacokinet Pharmacodyn 2018 Aug 26;45(4):537-555. Epub 2018 Mar 26.

Department of Mathematics and Statistics, University of Reading, Reading, RG6 6AX, UK.

In 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. Read More

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http://dx.doi.org/10.1007/s10928-018-9584-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061126PMC
August 2018
5 Reads