Interethnic Differences in Drug Disposition and Response: Relevance for Drug Development, Licensing, and Registration

1994 ◽  
pp. 233-263 ◽  
Author(s):  
L. P. Balant ◽  
P. G. Welling
Keyword(s):  
Drug Development ◽  
Drug Disposition ◽  
Interethnic Differences

A systematic review of the evidence supporting post-operative medication use in congenital heart disease

2021 ◽  
pp. 1-27
Author(s):  
Elizabeth J. Thompson ◽  
Henry P. Foote ◽  
Caitlin E. King ◽  
Sabarish Srinivasan ◽  
Elizabeth C. Ciociola ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Adverse Events ◽  
Drug Development ◽  
Drug Disposition ◽  
Controlled Vocabulary ◽  
Coagulation System ◽  
Future Research ◽  
Pulmonary Vasodilators ◽  
Post Operative Period ◽  
Operative Care

Abstract Background: Targeted drug development efforts in patients with CHD are needed to standardise care, improve outcomes, and limit adverse events in the post-operative period. To identify major gaps in knowledge that can be addressed by drug development efforts and provide a rationale for current clinical practice, this review evaluates the evidence behind the most common medication classes used in the post-operative care of children with CHD undergoing cardiac surgery with cardiopulmonary bypass. Methods: We systematically searched PubMed and EMBASE from 2000 to 2019 using a controlled vocabulary and keywords related to diuretics, vasoactives, sedatives, analgesics, pulmonary vasodilators, coagulation system medications, antiarrhythmics, steroids, and other endocrine drugs. We included studies of drugs given post-operatively to children with CHD undergoing repair or palliation with cardiopulmonary bypass. Results: We identified a total of 127 studies with 51,573 total children across medication classes. Most studies were retrospective cohorts at single centres. There is significant age- and disease-related variability in drug disposition, efficacy, and safety. Conclusion: In this study, we discovered major gaps in knowledge for each medication class and identified areas for future research. Advances in data collection through electronic health records, novel trial methods, and collaboration can aid drug development efforts in standardising care, improving outcomes, and limiting adverse events in the post-operative period.

The Role of P-Glycoprotein in Drug Disposition: Significance to Drug Development

2019 ◽  
pp. 359-434
Author(s):  
Matthew D. Troutman ◽  
Gang Luo ◽  
Beverly M. Knight ◽  
Dhiren R. Thakker ◽  
Liang-Shang Gan
Keyword(s):  
Drug Development ◽  
Drug Disposition ◽  
P Glycoprotein

Abstract 2933: Application of a mouse model humanized for the major pathways of drug disposition in anticancer drug development and use

2019 ◽  
Author(s):  
Colin J. Henderson ◽  
Nico Scheer ◽  
Yury Kapelyukh ◽  
Aileen McLaren ◽  
Kenneth MacLeod ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Development ◽  
Anticancer Drug ◽  
Drug Disposition ◽  
Anticancer Drug Development

scholarly journals Kidney Transporters and Drug-Induced Injury in Drug Development

2020 ◽  
Vol 48 (6) ◽  
pp. 721-724
Author(s):  
Zaher A. Radi
Keyword(s):  
Drug Development ◽  
Drug Disposition ◽  
Apical Membrane ◽  
Basolateral Membrane ◽  
Efflux Transporters ◽  
Pharmaceutical Drugs ◽  
Proximal Tubular Cells ◽  
Drug Induced ◽  
Tubular Cells ◽  
Proximal Tubular

Influx and efflux kidney tubular transporters are major determinants of the disposition of xenobiotics, including pharmaceutical drugs. On the basolateral membrane of proximal tubular cells, there are influx transporters, such as organic cation transporters. On the apical membrane of proximal tubular cells, there are efflux transporters, such as multidrug and toxin extrusion proteins. The secretion process across the apical membrane into the lumen occurs via efflux transporters which plays an important role in serum creatinine (sCr) elimination in urine. The interference of a pharmaceutical drug with transporters can lead to changes in sCr with no alterations in biomarkers or light microscopic evidence indicative of renal injury. Identification of transporters that influence drug disposition, toxicity, and overall nonclinical safety assessment is important in drug discovery and development programs. This mini review describes some key aspects of kidney tubular transporters and drug-induced renal toxicities in safety risk assessment and drug development.

scholarly journals A physiome interoperability roadmap for personalized drug development

2016 ◽  
Vol 6 (2) ◽  
pp. 20150094 ◽  
Author(s):  
Simon Thomas ◽  
Katherine Wolstencroft ◽  
Bernard de Bono ◽  
Peter J. Hunter
Keyword(s):  
Personalized Medicine ◽  
Drug Development ◽  
Drug Disposition ◽  
Model Development ◽  
Simulation Models ◽  
Individual Variability ◽  
Current Status ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Data Usability

The goal of developing therapies and dosage regimes for characterized subgroups of the general population can be facilitated by the use of simulation models able to incorporate information about inter-individual variability in drug disposition (pharmacokinetics), toxicity and response effect (pharmacodynamics). Such observed variability can have multiple causes at various scales, ranging from gross anatomical differences to differences in genome sequence. Relevant data for many of these aspects, particularly related to molecular assays (known as ‘-omics’), are available in online resources, but identification and assignment to appropriate model variables and parameters is a significant bottleneck in the model development process. Through its efforts to standardize annotation with consequent increase in data usability, the human physiome project has a vital role in improving productivity in model development and, thus, the development of personalized therapy regimes. Here, we review the current status of personalized medicine in clinical practice, outline some of the challenges that must be overcome in order to expand its applicability, and discuss the relevance of personalized medicine to the more widespread challenges being faced in drug discovery and development. We then review some of (i) the key data resources available for use in model development and (ii) the potential areas where advances made within the physiome modelling community could contribute to physiologically based pharmacokinetic and physiologically based pharmacokinetic/pharmacodynamic modelling in support of personalized drug development. We conclude by proposing a roadmap to further guide the physiome community in its on-going efforts to improve data usability, and integration with modelling efforts in the support of personalized medicine development.

scholarly journals Practical unidentifiability of receptor density in target mediated drug disposition models can lead to over-interpretation of drug concentration data

2017 ◽  
Author(s):  
Andrew M Stein
Keyword(s):  
Monoclonal Antibodies ◽  
Drug Development ◽  
Drug Concentration ◽  
Drug Disposition ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Receptor Density ◽  
Concentration Data ◽  
Human Dose ◽  
Target Mediated Drug Disposition

AbstractFor monoclonal antibodies, mathematical models of target mediated drug disposition (TMDD) are often fit to data in order to estimate key physiological parameters of the system. These parameter estimates can then be used to support drug development by assisting with the assessment of whether the target is druggable and what the first in human dose should be. The TMDD model is almost always over-parameterized given the available data, resulting in the practical unidentifiability of some of the model parameters, including the target receptor density. In particular, when only PK data is available, the receptor density is almost always practically unidentifiable. However, because practical identifiability is not regularly assessed, incorrect interpretation of model fits to the data can be made. This issue is illustrated using two case studies from the literature.

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