scholarly journals Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice

2021 ◽  
Vol 71 (4) ◽  
pp. 336-353
Author(s):  
Maša Roganović ◽  
Ana Homšek ◽  
Marija Jovanović ◽  
Valentina Topić-Vučenović ◽  
Milica Ćulafić ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Drug Development ◽  
Current Knowledge ◽  
European Medicines Agency ◽  
Population Pharmacokinetic ◽  
Population Modelling ◽  
Dose Individualisation ◽  
Regulatory Bodies ◽  
Development Phases ◽  
Modelling Approach

Due to frequent clinical trial failures and consequently fewer new drug approvals, the need for improvement in drug development has, to a certain extent, been met using model-based drug development. Pharmacometrics is a part of pharmacology that quantifies drug behaviour, treatment response and disease progression based on different models (pharmacokinetic - PK, pharmacodynamic - PD, PK/PD models, etc.) and simulations. Regulatory bodies (European Medicines Agency, Food and Drug Administration) encourage the use of modelling and simulations to facilitate decision-making throughout all drug development phases. Moreover, the identification of factors that contribute to variability provides a basis for dose individualisation in routine clinical practice. This review summarises current knowledge regarding the application of pharmacometrics in drug development and clinical practice with emphasis on the population modelling approach.

scholarly journals An Algorithm for Nonparametric Estimation of a Multivariate Mixing Distribution with Applications to Population Pharmacokinetics

Pharmaceutics ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 42
Author(s):  
Walter M. Yamada ◽  
Michael N. Neely ◽  
Jay Bartroff ◽  
David S. Bayard ◽  
James V. Burke ◽  
...  
Keyword(s):  
Drug Development ◽  
Population Pharmacokinetics ◽  
Empirical Bayes ◽  
Applied Mathematics ◽  
Grid Method ◽  
Bayes Estimation ◽  
Population Pharmacokinetic ◽  
Support Points ◽  
Primal Dual ◽  
Log Normal

Population pharmacokinetic (PK) modeling has become a cornerstone of drug development and optimal patient dosing. This approach offers great benefits for datasets with sparse sampling, such as in pediatric patients, and can describe between-patient variability. While most current algorithms assume normal or log-normal distributions for PK parameters, we present a mathematically consistent nonparametric maximum likelihood (NPML) method for estimating multivariate mixing distributions without any assumption about the shape of the distribution. This approach can handle distributions with any shape for all PK parameters. It is shown in convexity theory that the NPML estimator is discrete, meaning that it has finite number of points with nonzero probability. In fact, there are at most N points where N is the number of observed subjects. The original infinite NPML problem then becomes the finite dimensional problem of finding the location and probability of the support points. In the simplest case, each point essentially represents the set of PK parameters for one patient. The probability of the points is found by a primal-dual interior-point method; the location of the support points is found by an adaptive grid method. Our method is able to handle high-dimensional and complex multivariate mixture models. An important application is discussed for the problem of population pharmacokinetics and a nontrivial example is treated. Our algorithm has been successfully applied in hundreds of published pharmacometric studies. In addition to population pharmacokinetics, this research also applies to empirical Bayes estimation and many other areas of applied mathematics. Thereby, this approach presents an important addition to the pharmacometric toolbox for drug development and optimal patient dosing.

scholarly journals Noncompaction Cardiomyopathy—History and Current Knowledge for Clinical Practice

2021 ◽  
Vol 10 (11) ◽  
pp. 2457
Author(s):  
Birgit J. Gerecke ◽  
Rolf Engberding
Keyword(s):  
Clinical Practice ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Clinical Patient ◽  
Noncompaction Cardiomyopathy ◽  
The Past ◽  
Wide Range ◽  
Morphological Variants ◽  
A Current ◽  
Healthy Persons

Noncompaction cardiomyopathy (NCCM) has gained increasing attention over the past twenty years, but in daily clinical practice NCCM is still rarely considered. So far, there are no generally accepted diagnostic criteria and some groups even refuse to acknowledge it as a distinct cardiomyopathy, and grade it as a variant of dilated cardiomyopathy or a morphological trait of different conditions. A wide range of morphological variants have been observed even in healthy persons, suggesting that pathologic remodeling and physiologic adaptation have to be differentiated in cases where this spongy myocardial pattern is encountered. Recent studies have uncovered numerous new pathogenetic and pathophysiologic aspects of this elusive cardiomyopathy, but a current summary and evaluation of clinical patient management are still lacking, especially to avoid mis- and overdiagnosis. Addressing this issue, this article provides an up to date overview of the current knowledge in classification, pathogenesis, pathophysiology, epidemiology, clinical manifestations and diagnostic evaluation, including genetic testing, treatment and prognosis of NCCM.

Is GRADE the Right Choice for Clinical Practice Guidelines Developed by the American Academy of Otolaryngology–Head and Neck Surgery Foundation?

2019 ◽  
Vol 161 (1) ◽  
pp. 3-5
Author(s):  
Andrés M. Bur ◽  
Richard M. Rosenfeld
Keyword(s):  
Clinical Practice ◽  
American Academy ◽  
Head And Neck ◽  
Clinical Practice Guidelines ◽  
Practice Guidelines ◽  
Current Knowledge ◽  
Clinical Care ◽  
Neck Surgery ◽  
Head And Neck Surgery ◽  
The Right

Clinical practice guidelines (CPGs), developed to inform clinicians, patients, and policy makers about what constitutes optimal clinical care, are one way of increasing implementation of evidence into clinical practice. Many factors must be considered by multidisciplinary guideline panels, including strength of available evidence, limitations of current knowledge, risks/benefits of interventions, patient values, and limited resources. Grading of Recommendations Assessment, Development and Evaluation (GRADE) is a framework for summarizing evidence that has been endorsed by many national and international organizations for developing CPGs. But is GRADE the right choice for CPGs developed by the American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF)? In this commentary, we will introduce GRADE, discuss its strengths and limitations, and address the question of what potential benefits GRADE might offer beyond existing methodology used by the AAO-HNSF in developing CPGs.

scholarly journals A Population Modelling Approach to Studying Age-Related Effects on Excitation-Contraction Coupling in Human Cardiomyocytes

2019 ◽  
Author(s):  
Arsenii Dokuchaev ◽  
Svyatoslav Khamzin ◽  
Olga Solovyova
Keyword(s):  
Experimental Data ◽  
Transient Outward Current ◽  
Model Parameters ◽  
Maximal Velocity ◽  
Population Modelling ◽  
Individual Parameter ◽  
Human Cardiomyocytes ◽  
Age Related ◽  
Age Related Changes ◽  
Modelling Approach

AbstractAgeing is the dominant risk factor for cardiovascular diseases. A great body of experimental data has been gathered on cellular remodelling in the Ageing myocardium from animals. Very few experimental data are available on age-related changes in the human cardiomyocyte. We have used our combined electromechanical model of the human cardiomyocyte and the population modelling approach to investigate the variability in the response of cardiomyocytes to age-related changes in the model parameters. To generate the model population, we varied nine model parameters and excluded model samples with biomarkers falling outside of the physiological ranges. We evaluated the response to age-related changes in four electrophysiological model parameters reported in the literature: reduction in the density of the K+ transient outward current, maximal velocity of SERCA, and an increase in the density of NaCa exchange current and CaL-type current. The sensitivity of the action potential biomarkers to individual parameter variations was assessed. Each parameter modulation caused an increase in APD, while the sensitivity of the model to changes in GCaL and Vmax_up was much higher than to those in the effects of Gto and KNaCa. Then 60 age-related sets of the four parameters were randomly generated and each set was applied to every model in the control population. We calculated the frequency of model samples with repolarisation anomalies (RA) and the shortening of the electro-mechanical window in the ageing model populations as an arrhythmogenic ageing score. The linear dependence of the score on the deviation of the parameters showed a high determination coefficient with the most significant impact due to the age-related change in the CaL current. The population-based approach allowed us to classify models with low and high risk of age-related RA and to predict risks based on the control biomarkers.

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