| 1. |
- Darwich, Adam S., et al.
(author)
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Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy
- 2021
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In: Annual Review of Pharmacology and Toxicology. - : Annual Reviews Inc.. - 0362-1642 .- 1545-4304. ; 61:36, s. 1-21
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Journal article (peer-reviewed)abstract
- Model-informed precision dosing (MIPD) has become synonymous with modern approaches forindividualizing drug therapy, in which the characteristics of each patient are considered as opposedto applying a one-size-fits-all alternative. This review provides a brief account of the currentknowledge, practices, and opinions on MIPD while defining an achievable vision for MIPDin clinical care based on available evidence.We begin with a historical perspective on variabilityin dose requirements and then discuss technical aspects of MIPD, including the need for clinicaldecision support tools, practical validation, and implementation of MIPD in health care.Wealso discuss novel ways to characterize patient variability beyond the common perceptions of geneticcontrol. Finally, we address current debates on MIPD from the perspectives of the new drugdevelopment, health-care economics, and drug regulations.
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| 2. |
- El-Katheeb, Eman, et al.
(author)
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Time to revisit Child-Pugh score as the basis for predicting drug clearance in hepatic impairment
- 2021
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In: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 54:4, s. 388-401
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Journal article (peer-reviewed)abstract
- BackgroundPrescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child-Pugh score. Child-Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity.AimsTo demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients.MethodsRelevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically-based pharmacokinetic (PBPK) modelling.ResultsPBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug-metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically-impaired populations. These variables might not correlate with Child-Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child-Pugh score.ConclusionsMany physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child-Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child-Pugh alternatives are recommended to allow better prediction of drug exposure.
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| 3. |
- Prasad, Bhagwat, et al.
(author)
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Quantitative proteomics for translational pharmacology and precision medicine : state of the art and future outlook
- 2024
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In: Drug Metabolism And Disposition. - 0090-9556 .- 1521-009X. ; 52:7
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Journal article (peer-reviewed)abstract
- Over the past 20 years, quantitative proteomics has contributed a wealth of protein expression data, which are currently used for a variety of systems pharmacology applications, as a complement or a surrogate for activity of the corresponding proteins. A symposium at the 25th North American ISSX meeting, in Boston, in September 2023, was held to explore current and emerging applications of quantitative proteomics in translational pharmacology and strategies for improved integration into model-informed drug development based on practical experience of each of the presenters. A summary of the talks and discussions is presented in this perspective alongside future outlooks that were outlined for future meetings.
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| 4. |
- Prasad, Bhagwat, et al.
(author)
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Toward a Consensus on Applying Quantitative Liquid Chromatography-Tandem Mass Spectrometry Proteomics in Translational Pharmacology Research : A White Paper
- 2019
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In: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 106:3, s. 525-543
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Journal article (peer-reviewed)abstract
- Quantitative translation of information on drug absorption, disposition, receptor engagement, and drug-drug interactions from bench to bedside requires models informed by physiological parameters that link in vitro studies to in vivo outcomes. To predict in vivo outcomes, biochemical data from experimental systems are routinely scaled using protein quantity in these systems and relevant tissues. Although several laboratories have generated useful quantitative proteomic data using state-of-the-art mass spectrometry, no harmonized guidelines exit for sample analysis and data integration to in vivo translation practices. To address this gap, a workshop was held on September 27 and 28, 2018, in Cambridge, MA, with 100 experts attending from academia, the pharmaceutical industry, and regulators. Various aspects of quantitative proteomics and its applications in translational pharmacology were debated. A summary of discussions and best practices identified by this expert panel are presented in this "White Paper" alongside unresolved issues that were outlined for future debates.
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| 5. |
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| 6. |
- Wegler, Christine, et al.
(author)
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Variability in Mass Spectrometry-based Quantification of Clinically Relevant Drug Transporters and Drug Metabolizing Enzymes
- 2017
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In: Molecular Pharmaceutics. - : AMER CHEMICAL SOC. - 1543-8384 .- 1543-8392. ; 14:9, s. 3142-3151
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Journal article (peer-reviewed)abstract
- Many different methods are used for mass-spectrometry-based protein quantification in pharmacokinetics and systems pharmacology. It has not been established to what extent the results from these various methods are comparable. Here, we compared six different mass spectrometry-based proteomics methods by measuring the expression of clinically relevant drug transporters and metabolizing enzymes in human liver. Mean protein concentrations were in general quantified to similar levels by methods using whole tissue lysates. Methods using subcellular membrane fractionation gave incomplete enrichment of the proteins. When the enriched proteins were adjusted to levels in whole tissue lysates, they were on average 4 fold lower than those quantified directly in whole tissue lysates. The differences in protein levels were propagated into differences in predictions of hepatic clearance. In conclusion, caution is needed when comparing and applying quantitative proteomics data obtained with different methods, especially since membrane fractionation is common practice for protein quantification used in drug clearance predictions.
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