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


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
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
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
4 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

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

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
10 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
February 2019
2 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
13 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
18 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
6 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
2 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
8 Reads

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

J Pharmacokinet Pharmacodyn 2018 Sep 14. 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
September 2018
10 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
3 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

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
8 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
16 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

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

J Pharmacokinet Pharmacodyn 2018 Jul 10. 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
July 2018
10 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 Jul 9. 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
July 2018
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
16 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
3 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
2 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
7 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
8 Reads

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

J Pharmacokinet Pharmacodyn 2018 May 7. 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
May 2018
9 Reads

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

J Pharmacokinet Pharmacodyn 2018 May 7. 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
May 2018
3 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
1 Read

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
5 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
2 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
3 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
10 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
5 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
4 Reads

Assessing QT/QTc interval prolongation with concentration-QT modeling for Phase I studies: impact of computational platforms, model structures and confidence interval calculation methods.

J Pharmacokinet Pharmacodyn 2018 Jun 19;45(3):469-482. Epub 2018 Mar 19.

Quantitative Clinical Pharmacology, IMED Biotech Unit, AstraZeneca Pharmaceuticals, Gatehouse Park, 35 Gatehouse Drive, Waltham, MA, 02451, USA.

Modeling the relationship between drug concentrations and heart rate corrected QT interval (QTc) change from baseline (C-∆QTc), based on Phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies, has been proposed as an alternative to thorough QT studies (TQT), in assessing drug-induced QT prolongation risk. The present analysis used clinical SAD, MAD and TQT study data of an experimental compound, AZD5672, to evaluate the performance of: (i) three computational platforms (linear mixed-effects modeling implemented via PROC MIXED in SAS, as well as in R using LME4 package and linear quantile mixed models (LQMM) implemented via LQMM package; (ii) different model structures with and without treatment- or time-specific intercepts; and (iii) three methods for calculating the confidence interval (CI) of QTc prolongation (analytical and bootstrap methods with fixed or varied geometric mean concentrations). We show that treatment- and time-specific intercepts may need to be included into C-∆QTc modeling through PROC MIXED or LME4, regardless of their statistical significance. Read More

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http://link.springer.com/10.1007/s10928-018-9582-0
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http://dx.doi.org/10.1007/s10928-018-9582-0DOI Listing
June 2018
20 Reads

A comprehensive evaluation of exposure-response relationships in clinical trials: application to support guselkumab dose selection for patients with psoriasis.

J Pharmacokinet Pharmacodyn 2018 Aug 16;45(4):523-535. Epub 2018 Mar 16.

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

Guselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator's Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure-response (E-R) modeling analyses, we sought to predict the guselkumab dose-response (D-R) relationship using data from 1459 patients who participated in these trials. A recently developed novel latent-variable Type I Indirect Response joint model was applied to PASI75/90/100 and IGA response thresholds, with placebo effect empirically modeled. Read More

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http://dx.doi.org/10.1007/s10928-018-9581-1DOI Listing
August 2018
35 Reads

Drug-physiology interaction and its influence on the QT prolongation-mechanistic modeling study.

J Pharmacokinet Pharmacodyn 2018 Jun 15;45(3):483-490. Epub 2018 Mar 15.

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

The current study is an example of drug-disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology-ten Tusscher ventricular cardiomyocyte cell model-was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Read More

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http://dx.doi.org/10.1007/s10928-018-9583-zDOI Listing
June 2018
3 Reads

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development.

J Pharmacokinet Pharmacodyn 2018 Jun 8;45(3):457-467. Epub 2018 Mar 8.

Critical Path Institute, 1730 E. River Road, Tucson, AZ, 85705, USA.

Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. Read More

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http://dx.doi.org/10.1007/s10928-018-9580-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953981PMC
June 2018
8 Reads

Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors.

J Pharmacokinet Pharmacodyn 2018 Jun 14;45(3):401-418. Epub 2018 Feb 14.

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

Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. Read More

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http://dx.doi.org/10.1007/s10928-018-9578-9DOI Listing
June 2018
8 Reads

Correction to: PK-PD Compass: bringing infectious diseases pharmacometrics to the patient's bedside.

J Pharmacokinet Pharmacodyn 2018 Apr;45(2):351

Institute for Clinical Pharmacodynamics (ICPD), 242 Broadway, Schenectady, NY, 12305, USA.

The original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum. Read More

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http://dx.doi.org/10.1007/s10928-018-9572-2DOI Listing
April 2018
3 Reads

Evaluation of performance of distributed delay model for chemotherapy-induced myelosuppression.

J Pharmacokinet Pharmacodyn 2018 Apr 12;45(2):329-337. Epub 2018 Feb 12.

Certara, Raleigh, NC, USA.

The distributed delay model has been introduced that replaces the transit compartments in the classic model of chemotherapy-induced myelosuppression with a convolution integral. The maturation of granulocyte precursors in the bone marrow is described by the gamma probability density function with the shape parameter (ν). If ν is a positive integer, the distributed delay model coincides with the classic model with ν transit compartments. Read More

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http://dx.doi.org/10.1007/s10928-018-9575-zDOI Listing
April 2018
3 Reads

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data.

J Pharmacokinet Pharmacodyn 2018 Jun 12;45(3):419-430. Epub 2018 Feb 12.

Duke Clinical Research Institute, Duke University School of Medicine, 2400 Pratt St, Durham, NC, 27705, USA.

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. Read More

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http://dx.doi.org/10.1007/s10928-018-9576-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955725PMC
June 2018
10 Reads

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens.

J Pharmacokinet Pharmacodyn 2018 Jun 10;45(3):431-442. Epub 2018 Feb 10.

Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek - The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. Read More

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http://dx.doi.org/10.1007/s10928-018-9579-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953989PMC
June 2018
8 Reads

Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model.

J Pharmacokinet Pharmacodyn 2018 Jun 9;45(3):443-456. Epub 2018 Feb 9.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, Dept. R4PK, Bldg. AP31-3, North Chicago, IL, 60064, USA.

Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. Read More

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http://dx.doi.org/10.1007/s10928-018-9574-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953987PMC
June 2018
2 Reads

A framework for 2-stage global sensitivity analysis of GastroPlus™ compartmental models.

J Pharmacokinet Pharmacodyn 2018 Apr 8;45(2):309-327. Epub 2018 Feb 8.

Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, NJ, 08854, USA.

Parameter sensitivity and uncertainty analysis for physiologically based pharmacokinetic (PBPK) models are becoming an important consideration for regulatory submissions, requiring further evaluation to establish the need for global sensitivity analysis. To demonstrate the benefits of an extensive analysis, global sensitivity was implemented for the GastroPlus™ model, a well-known commercially available platform, using four example drugs: acetaminophen, risperidone, atenolol, and furosemide. The capabilities of GastroPlus were expanded by developing an integrated framework to automate the GastroPlus graphical user interface with AutoIt and for execution of the sensitivity analysis in MATLAB. Read More

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http://dx.doi.org/10.1007/s10928-018-9573-1DOI Listing
April 2018
7 Reads
1.460 Impact Factor

Establishing in vitro-in vivo correlation for antibody drug conjugate efficacy: a PK/PD modeling approach.

J Pharmacokinet Pharmacodyn 2018 Apr 8;45(2):339-349. Epub 2018 Feb 8.

Translational Research Group, Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT, 06340, USA.

The objective of this manuscript was to establish in vitro-in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. Read More

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http://link.springer.com/10.1007/s10928-018-9577-x
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http://dx.doi.org/10.1007/s10928-018-9577-xDOI Listing
April 2018
22 Reads
1.460 Impact Factor

How to mathematically optimize drug regimens using optimal control.

Authors:
Helen Moore

J Pharmacokinet Pharmacodyn 2018 Feb 6;45(1):127-137. Epub 2018 Feb 6.

Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ, 08543, USA.

This article gives an overview of a technique called optimal control, which is used to optimize real-world quantities represented by mathematical models. I include background information about the historical development of the technique and applications in a variety of fields. The main focus here is the application to diseases and therapies, particularly the optimization of combination therapies, and I highlight several such examples. Read More

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http://dx.doi.org/10.1007/s10928-018-9568-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847021PMC
February 2018
1 Read