Accounting for inter-correlation between enzyme abundance: a simulation study to assess implications on global sensitivity analysis within physiologically-based pharmacokinetics

AbstractPhysiologically based pharmacokinetic (PBPK) models often include several sets of correlated parameters, such as organ volumes and blood flows. Because of recent advances in proteomics, it has been demonstrated that correlations are also present between abundances of drug-metabolising enzymes in the liver. As the focus of population PBPK has shifted the emphasis from the average individual to theoretically conceivable extremes, reliable estimation of the extreme cases has become paramount. We performed a simulation study to assess the impact of the correlation between the abundances of two enzymes on the pharmacokinetics of drugs that are substrate of both, under assumptions of presence or lack of such correlations. We considered three semi-physiological models representing the cases of: (1) intravenously administered drugs metabolised by two enzymes expressed in the liver; (2) orally administered drugs metabolised by CYP3A4 expressed in the liver and gut wall; (3) intravenously administered drugs that are substrates of CYP3A4 and OATP1B1 in the liver. Finally, the impact of considering or ignoring correlation between enzymatic abundances on global sensitivity analysis (GSA) was investigated using variance based GSA on a reduced PBPK model for repaglinide, substrate of CYP3A4 and CYP2C8. Implementing such correlations can increase the confidence interval for population pharmacokinetic parameters (e.g., AUC, bioavailability) and impact the GSA results. Ignoring these c...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

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This article describes a split luciferase complementation (SLC) method designed to discover inhibitors of protein-protein interaction. Different fusion proteins with split luciferase are constructed, expressed, and purified, and then assessed to determine the best pair that generates the strongest luminescence. SLC specificity and affinity are further confirmed. Step-by-step instructions are provided for performing these assays using the NS2B-NS3 interaction as an example. NS2B is an essential cofactor for flaviviral NS3 protease function. Advantages and disadvantages of these assays are further discussed. © 2019 by J...
Source: Current Protocols in Toxicology - Category: Toxicology Tags: Curr Protoc Toxicol Source Type: research
Publication date: Available online 6 December 2019Source: American Journal of Kidney DiseasesAuthor(s): Yu-Ji Lee, Yusuke Okuda, John Sy, Yong Kyu Lee, Yoshitsugu Obi, Seong Cho, Joline L.T. Chen, Anna Jin, Connie M. Rhee, Kamyar Kalantar-Zadeh, Elani StrejaRationale &ObjectivePatients receiving twice-weekly or less-frequent hemodialysis (HD) may need to undergo higher ultrafiltration rates (UFRs) to maintain acceptable fluid balance. We hypothesized that higher UFRs are associated with faster decline in residual kidney function (RKF) and a higher rate of mortality.Study DesignRetrospective cohort study.Setting &Pa...
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
Publication date: Available online 6 December 2019Source: American Journal of Kidney DiseasesAuthor(s): Junichi Ishigami, Yingying Sang, Morgan E. Grams, Josef Coresh, Alex Chang, Kunihiro MatsushitaRationale &ObjectiveInfluenza vaccination is recommended for all adults but particularly for older adults and those with high-risk conditions. Reduced kidney function is an important high-risk condition, but the effectiveness of influenza vaccination across kidney function is uncharacterized. We assessed the effectiveness of influenza vaccination among older adults with and without reduced kidney function.Study DesignObserv...
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
The number of women who die in the U.S. because of complications related to pregnancy is shockingly high – nearly 30 deaths for every 100,000 births each year. But some women die at higher rates than others: the maternal mortality rate for black women is three to four times higher than it is for white women. On this episode of The Dose, the Commonwealth Fund’s Laurie Zephyrin, M.D., and Akeiisa Coleman talk about one way to address this crisis: Medicaid, which pays for nearly half the 4 million births in the U.S. each year. States have a real opportunity, they say, to take innovative steps to improve the care ...
Source: The Commonwealth Fund: Publications - Category: International Medicine & Public Health Authors: Source Type: research
Population Health Management, Ahead of Print.
Source: Population Health Management - Category: International Medicine & Public Health Authors: Source Type: research
Population Health Management, Ahead of Print.
Source: Population Health Management - Category: International Medicine & Public Health Authors: Source Type: research
Publication date: Available online 5 December 2019Source: The Lancet Global HealthAuthor(s): Sandeep P Kishore, Usnish B Majumdar
Source: The Lancet Global Health - Category: International Medicine & Public Health Source Type: research
Publication date: Available online 5 December 2019Source: The Lancet Global HealthAuthor(s): The Lancet Global Health
Source: The Lancet Global Health - Category: International Medicine & Public Health Source Type: research
Publication date: Available online 5 December 2019Source: The Lancet Global HealthAuthor(s): Luke N Allen, Brian D Nicholson, Beatrice Y T Yeung, Francisco Goiana-da-SilvaSummaryBackgroundMost countries have endorsed WHO non-communicable disease (NCD) best buy policies, but we know very little about global implementation patterns and about the geopolitical factors affecting implementation. We aimed to assess global implementation based on analysis of multiple geopolitical datasets.MethodsWe used the 2015 and 2017 WHO NCD progress monitor reports to calculate aggregate implementation scores for 151 countries, based on their...
Source: The Lancet Global Health - Category: International Medicine & Public Health Source Type: research
Publication date: Available online 6 December 2019Source: Preventive MedicineAuthor(s): Elisabeth R. Silver, Chin HurAbstractThe majority of research on gender and the opioid epidemic focuses on women as patients, caregivers, or expectant mothers. However, little research approaches men as gendered subjects, despite their dramatically increased risk of opioid overdose. Accordingly, we examined gender differences in prescription opioid use and misuse with specific attention to implications for men using data from the 2017 National Survey on Drug Use and Health. We used design-adjusted, weighted Wald tests and multivariate l...
Source: Preventive Medicine - Category: International Medicine & Public Health Source Type: research
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