scholarly journals Individualized treatment strategies for hyperuricemia informed by a semi-mechanistic exposure-response model of uric acid dynamics

2018 ◽  
Vol 6 (5) ◽  
pp. e13614 ◽  
Author(s):  
Sergey Aksenov ◽  
Carl C. Peck ◽  
Ulf G. Eriksson ◽  
Donald R. Stanski
Keyword(s):  
Uric Acid ◽  
Treatment Strategies ◽  
Individualized Treatment ◽  
Response Model ◽  
Exposure Response

scholarly journals A semi-mechanistic exposure–response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases

2021 ◽  
Author(s):  
Jacob Leander ◽  
Mikael Sunnåker ◽  
Dinko Rekić ◽  
Sergey Aksenov ◽  
Ulf G. Eriksson ◽  
...  
Keyword(s):  
Uric Acid ◽  
Healthy Volunteers ◽  
Acid Production ◽  
Treatment Strategies ◽  
Oxidase Inhibitor ◽  
Response Model ◽  
Xanthine Oxidase Inhibitor ◽  
Exposure Response ◽  
Significant Difference ◽  
The Impact

AbstractVerinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure–response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose–response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad.

scholarly journals Exposure-Response Model of Subcutaneous C1-Inhibitor Concentrate to Estimate the Risk of Attacks in Patients With Hereditary Angioedema

2018 ◽  
Vol 7 (3) ◽  
pp. 158-165 ◽  
Author(s):  
Ying Zhang ◽  
Michael A. Tortorici ◽  
Dipti Pawaskar ◽  
Ingo Pragst ◽  
Thomas Machnig ◽  
...  
Keyword(s):  
Hereditary Angioedema ◽  
Response Model ◽  
C1 Inhibitor ◽  
Exposure Response

scholarly journals Extrapolation of a Brivaracetam Exposure–Response Model from Adults to Children with Focal Seizures

2017 ◽  
Vol 57 (7) ◽  
pp. 843-854 ◽  
Author(s):  
Rik Schoemaker ◽  
Janet R. Wade ◽  
Armel Stockis
Keyword(s):  
Response Model ◽  
Focal Seizures ◽  
Exposure Response

Comment: Outcome-Wide Individualized Treatment Strategies

2020 ◽  
Vol 35 (3) ◽  
pp. 472-475
Author(s):  
Ashkan Ertefaie ◽  
Brent A. Johnson
Keyword(s):  
Treatment Strategies ◽  
Individualized Treatment

scholarly journals The promise of the gut microbiome as part of individualized treatment strategies

2021 ◽  
Author(s):  
Daniel A. Schupack ◽  
Ruben A. T. Mars ◽  
Dayne H. Voelker ◽  
Jithma P. Abeykoon ◽  
Purna C. Kashyap
Keyword(s):  
Gut Microbiome ◽  
Treatment Strategies ◽  
Individualized Treatment

The Temporal Dynamics of Ozone-Induced FEV1Changes in Humans: An Exposure-Response Model

2007 ◽  
Vol 19 (6-7) ◽  
pp. 483-494 ◽  
Author(s):  
William F. McDonnell ◽  
Paul W. Stewart ◽  
Marjo V. Smith
Keyword(s):  
Temporal Dynamics ◽  
Response Model ◽  
Exposure Response

scholarly journals Exposure-Response Modeling to Support Dosing Selection for Phase IIb Development of Kukoamine B in Sepsis Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Huanhuan Wang ◽  
Xiaoyun Hu ◽  
Teng Wang ◽  
Cheng Cui ◽  
Ji Jiang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Sofa Score ◽  
Standard Care ◽  
Goodness Of Fit ◽  
Response Model ◽  
Mixed Effect ◽  
Exposure Response ◽  
Therapy Effect ◽  
Selection For ◽  
The Impact

Aim: Kukoamine B, a small molecule compound, is being developed for the treatment of sepsis in a Phase II clinical trial. The objective of this study was to optimize dosing selection for a Phase IIb clinical trial using an exposure-response model.Methods: Data of 34 sepsis patients from a Phase IIa clinical trial were used in the model: 10 sepsis patients from the placebo group and a total of 24 sepsis patients from the 0.06 mg/kg, 0.12 mg/kg, and 0.24 mg/kg drug groups. Exposure-response relationship was constructed to model the impact of the standard care therapy and area under curve (AUC) of kukoamine B to the disease biomarker (SOFA score). The model was evaluated by goodness of fit and visual predictive check. The simulation was performed 1,000 times based on the built model.Results: The data of the placebo and the drug groups were pooled and modeled by a nonlinear mixed-effect modeling approach in sepsis. A latent-variable approach in conjunction with an inhibitory indirect response model was used to link the standard care therapy effect and drug exposure to SOFA score. The maximum fraction of the standard care therapy was estimated to 0.792. The eliminate rate constant of the SOFA score was 0.263/day for the standard care therapy. The production rate of SOFA score (Kin) was estimated at 0.0569/day and the AUC at half the maximal drug effect (EAUC50) was estimated at 1,320 h*ng/mL. Model evaluation showed that the built model could well describe the observed SOFA score. Model-based simulations showed that the SOFA score on day 7 decreased to a plateau when AUC increased to 1,500 h*ng/mL.Conclusion: We built an exposure-response model characterizing the pharmacological effect of kukoamine B from the standard care therapy in sepsis patients. A dose regimen of 0.24 mg/kg was finally recommended for the Phase IIb clinical trial of kukoamine B based on modeling and simulation results.

Testing Extrapolation of a Biologically Based Exposure–Response Model from in Vitro to in Vivo Conditions

2002 ◽  
Vol 35 (1) ◽  
pp. 72-79 ◽  
Author(s):  
M. Mebust ◽  
D. Crawford-Brown ◽  
W. Hofmann ◽  
H. Schöllnberger
Keyword(s):  
Response Model ◽  
Exposure Response
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