Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems

AbstractGuiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric (Stein and Ramakrishna in CPT Pharmacomet Syst Pharmacol 6(4):258 –266, 2017) is extended to include a “target-tissue” compartment and the shedding of membrane-bound targets. A new potency metric average free tissue target to initial target ratio (AFTIR) at steady state is derived, and it depends on only four key quantities: the equilibrium binding constant, the fold-change in target expression at steady state after binding to drug, the biodistribution of target from circulation to target tissue, and the average drug concentration in circulation. The AFTIR metric is useful for guiding dose selection, for efficiently performing sensitivity analyses, and for building intuition for more complex target mediated drug disposition models. In particular, reducing the complex, physiological model to four key parameters needed to predict target inhibition helps to highlight specific parameters that are the most important to estimate in future experiments t o guide drug development.
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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