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Journal of Pharmacokinetics and Pharmacodynamics

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https://www.readbyqxmd.com/read/28316019/population-pharmacokinetic-analysis-of-rebamipide-in-healthy-korean-subjects-with-the-characterization-of-atypical-complex-absorption-kinetics
#1
Lien Ngo, Hee-Doo Yoo, Phuong Tran, Hea-Young Cho, Yong-Bok Lee
In this study, the population pharmacokinetic (PK) analysis of rebamipide (Reba) in healthy male Korean subjects was analyzed using the nonlinear mixed effects modeling method. The possible effects of physiological covariates and the multidrug resistance (MDR1) gene 3435C>T polymorphism on PK parameters were also investigated. Data were collected from a bioequivalence study, in which 26 subjects who participated in the study were administered a single oral dose of 100 mg Reba; only data from the reference formulation were used...
March 18, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28299529/modeling-and-simulation-in-dose-determination-for-biodefense-products-approved-under-the-fda-animal-rule
#2
Kimberly L Bergman, K Krudys, S K Seo, J Florian
Development of effective medical countermeasures for biodefense is vital to United States biopreparedness and response in the age of terrorism, both foreign and domestic. A traditional drug development pathway toward approval is not possible for most biodefense-related indications, creating the need for alternative development pathways such as the FDA's Animal Rule. Under this unique regulatory mechanism, FDA-approval is based on adequate and well-controlled animal studies when it is neither ethical nor feasible to conduct human efficacy studies...
March 15, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28283865/editorial-to-the-themed-issue-on-focus-on-infectious-disease
#3
EDITORIAL
Peter Bonate
No abstract text is available yet for this article.
March 10, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28260166/population-pbpk-modelling-of-trastuzumab-a-framework-for-quantifying-and-predicting-inter-individual-variability
#4
Paul R V Malik, Abdullah Hamadeh, Colin Phipps, Andrea N Edginton
In this work we proposed a population physiologically-based pharmacokinetic (popPBPK) framework for quantifying and predicting inter-individual pharmacokinetic variability using the anti-HER2 monoclonal antibody (mAb) trastuzumab as an example. First, a PBPK model was developed to account for the possible mechanistic sources of variability. Within the model, five key factors that contribute to variability were identified and the nature of their contribution was quantified with local and global sensitivity analyses...
March 4, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28251386/exposure-disease-response-analysis-of-natalizumab-in-subjects-with-multiple-sclerosis
#5
Kumar Kandadi Muralidharan, Deb Steiner, Diogo Amarante, Pei-Ran Ho, Dan Mikol, Jacob Elkins, Meena Subramanyam, Ivan Nestorov
Natalizumab, a human immunoglobulin monoclonal antibody that targets α4β1/α4β7 integrin, is an effective therapy approved for the treatment of multiple sclerosis (MS). The objective of this analysis was to develop a population exposure-response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response...
March 1, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28224315/modeling-of-free-fatty-acid-dynamics-insulin-and-nicotinic-acid-resistance-under-acute-and-chronic-treatments
#6
Robert Andersson, Tobias Kroon, Joachim Almquist, Mats Jirstrand, Nicholas D Oakes, Neil D Evans, Michael J Chappel, Johan Gabrielsson
Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc-FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework...
February 21, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28214989/exposure-response-analyses-of-blood-pressure-and-heart-rate-changes-for-methylphenidate-in-healthy-adults
#7
Liang Li, Yaning Wang, Ramana S Uppoor, Mehul U Mehta, Tiffany Farchione, Mitchell V Mathis, Hao Zhu
The aim of the study was to evaluate the exposure-response (E-R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E-R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check...
February 18, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28205025/the-multistate-tuberculosis-pharmacometric-model-a-semi-mechanistic-pharmacokinetic-pharmacodynamic-model-for-studying-drug-effects-in-an-acute-tuberculosis-mouse-model
#8
Chunli Chen, Fatima Ortega, Joaquin Rullas, Laura Alameda, Iñigo Angulo-Barturen, Santiago Ferrer, Ulrika Sh Simonsson
The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day)...
February 15, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28194623/comparison-of-non-compartmental-and-mixed-effect-modelling-methods-for-establishing-bioequivalence-for-the-case-of-two-compartment-kinetics-and-censored-concentrations
#9
Jim H Hughes, Richard N Upton, David J R Foster
Non-compartmental analysis (NCA) is regarded as the standard for establishing bioequivalence, despite its limitations and the existence of alternative methods such as non-linear mixed effects modelling (NLMEM). Comparisons of NCA and NLMEM in bioequivalence testing have been limited to drugs with one-compartment kinetics and have included a large number of different approaches. A simulation tool was developed with the ability to rapidly compare NCA and NLMEM methods in determining bioequivalence using both R and NONMEM and applied to a drug with two-compartment pharmacokinetics...
February 13, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28194555/nonlinear-mixed-effects-models-for-pharmacokinetic-data-analysis-assessment-of-the-random-effects-distribution
#10
Reza Drikvandi
Nonlinear mixed-effects models are frequently used for pharmacokinetic data analysis, and they account for inter-subject variability in pharmacokinetic parameters by incorporating subject-specific random effects into the model. The random effects are often assumed to follow a (multivariate) normal distribution. However, many articles have shown that misspecifying the random-effects distribution can introduce bias in the estimates of parameters and affect inferences about the random effects themselves, such as estimation of the inter-subject variability...
February 13, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28181136/prognostic-value-of-galactomannan-current-evidence-for-monitoring-response-to-antifungal-therapy-in-patients-with-invasive-aspergillosis
#11
REVIEW
Laura L Kovanda, Amit V Desai, William W Hope
Galactomannan (GM) is a polysaccharide present in the cell wall of Aspergillus spp. that is released during growth of the organism. It has been successfully used to aide in the diagnosis of invasive aspergillosis allowing for earlier recognition of disease compared to conventional methods. Since its implementation in the clinic as a diagnostic tool, GM has been used in experimental models to measure therapeutic response. Several clinical studies describe the prognostic value of GM. Herein, we review the evidence supporting the utilization of GM antigen as a biomarker to measure response to systemic antifungal therapy...
February 8, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28161807/what-we-may-expect-from-novel-antibacterial-agents-in-the-pipeline-with-respect-to-resistance-and-pharmacodynamic-principles
#12
REVIEW
Karen Bush, Malcolm G P Page
There are some 43 small molecules in the antibiotic development pipeline from late preclinical stage (7 compounds) through Phase 1 (11 molecules), Phase 2 (13 molecules) to Phase 3 (12 molecules). The majority of these are representatives of established antibiotic classes that have been modified to address problems of resistance. In addition, there is considerable activity around the discovery of novel classes of β-lactamase inhibitors with 10 combinations representing 4 inhibitor classes, at different stages of development...
February 4, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28150181/empirical-models-for-fitting-of-oral-concentration-time-curves-with-and-without-an-intravenous-reference
#13
Michael Weiss
Appropriate model selection is important in fitting oral concentration-time data due to the complex character of the absorption process. When IV reference data are available, the problem is the selection of an empirical input function (absorption model). In the present examples a weighted sum of inverse Gaussian density functions (IG) was found most useful. It is shown that alternative models (gamma and Weibull density) are only valid if the input function is log-concave. Furthermore, it is demonstrated for the first time that the sum of IGs model can be also applied to fit oral data directly (without IV data)...
February 1, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28132162/population-pharmacokinetics-and-pharmacodynamics-of-ionis-gcgrrx-an-antisense-oligonucleotide-for-type-2-diabetes-mellitus-a-red-blood-cell-lifespan-model
#14
Kenneth T Luu, Erin S Morgan, Sanjay Bhanot, Richard Geary, Anne Smith, Claudette Bethune, Lynnetta Watts, Scott Henry, Yanfeng Wang
IONIS-GCGRRx (ISIS 449884) is an antisense oligonucleotide inhibitor of the glucagon receptor (GCGR). The objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-GCGRRx via population-based modeling. The observed data were obtained from a Phase 1 (50, 100, 200, 300 and 400 mg) single- and multiple-dose study in healthy volunteers and a Phase 2 (100 and 200 mg) multiple-dose study in T2DM patients. The PK of IONIS GCGRRx was characterized by two primary systemic compartments and three absorption transit compartments with elimination out of the peripheral compartment...
January 28, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28144841/adjusted-adaptive-lasso-for-covariate-model-building-in-nonlinear-mixed-effect-pharmacokinetic-models
#15
Elham Haem, Kajsa Harling, Seyyed Mohammad Taghi Ayatollahi, Najaf Zare, Mats O Karlsson
One important aim in population pharmacokinetics (PK) and pharmacodynamics is identification and quantification of the relationships between the parameters and covariates. Lasso has been suggested as a technique for simultaneous estimation and covariate selection. In linear regression, it has been shown that Lasso possesses no oracle properties, which means it asymptotically performs as though the true underlying model was given in advance. Adaptive Lasso (ALasso) with appropriate initial weights is claimed to possess oracle properties; however, it can lead to poor predictive performance when there is multicollinearity between covariates...
February 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28074396/target-mediated-drug-disposition-with-drug-drug-interaction-part-ii-competitive-and-uncompetitive-cases
#16
Gilbert Koch, William J Jusko, Johannes Schropp
We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions...
February 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28074395/target-mediated-drug-disposition-with-drug-drug-interaction-part-i-single-drug-case-in-alternative-formulations
#17
Gilbert Koch, William J Jusko, Johannes Schropp
Target-mediated drug disposition (TMDD) describes drug binding with high affinity to a target such as a receptor. In application TMDD models are often over-parameterized and quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are essential to reduce the number of parameters. However, implementation of such approximations becomes difficult for TMDD models with drug-drug interaction (DDI) mechanisms. Hence, alternative but equivalent formulations are necessary for QE or QSS approximations. To introduce and develop such formulations, the single drug case is reanalyzed...
February 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28063122/drug-disposition-model-of-radiolabeled-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-on-hemodialysis
#18
Liviawati Wu, Murad Melhem, Raju Subramanian, Benjamin Wu
Etelcalcetide (AMG 416) is an allosteric activator of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. To characterize the time course of etelcalcetide in different matrices (plasma, dialysate, urine, and feces), a drug disposition model was developed. Nonlinear mixed-effect modeling was used to describe data from six adults with CKD on hemodialysis who received a single intravenous dose of [(14)C]etelcalcetide (10 mg; 710 nCi) after hemodialysis (study NCT02054572)...
February 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28050672/impact-of-saturable-distribution-in-compartmental-pk-models-dynamics-and-practical-use
#19
Lambertus A Peletier, Willem de Winter
We explore the impact of saturable distribution over the central and the peripheral compartment in pharmacokinetic models, whilst assuming that back flow into the central compartiment is linear. Using simulations and analytical methods we demonstrate characteristic tell-tale differences in plasma concentration profiles of saturable versus linear distribution models, which can serve as a guide to their practical applicability. For two extreme cases, relating to (i) the size of the peripheral compartment with respect to the central compartment and (ii) the magnitude of the back flow as related to direct elimination from the central compartment, we derive explicit approximations which make it possible to give quantitative estimates of parameters...
February 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27909942/experiment-design-for-nonparametric-models-based-on-minimizing-bayes-risk-application-to-voriconazole-formula-see-text
#20
David S Bayard, Michael Neely
An experimental design approach is presented for individualized therapy in the special case where the prior information is specified by a nonparametric (NP) population model. Here, a NP model refers to a discrete probability model characterized by a finite set of support points and their associated weights. An important question arises as to how to best design experiments for this type of model. Many experimental design methods are based on Fisher information or other approaches originally developed for parametric models...
December 1, 2016: Journal of Pharmacokinetics and Pharmacodynamics
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