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

Physiological Reports
Sergey AksenovDonald R Stanski

Abstract

To provide insight into pharmacological treatment of hyperuricemia we developed a semi-mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR, FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co-administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a...Continue Reading

References

May 1, 1968·Metabolism: Clinical and Experimental·J J McPhaul
Oct 1, 1965·Arthritis and Rheumatism·L B Sorensen
Apr 1, 1996·British Journal of Clinical Pharmacology·S GrahamD J Birkett
Mar 18, 2000·Kidney International·M ZiółkoJ Grabska-Chrzastowska
Nov 1, 1954·The American Journal of Physiology·L G WESSON
Jun 19, 2004·Current Opinion in Nephrology and Hypertension·Naim M MaaloufKhashayar Sakhaee
Mar 18, 2005·Physiology·Matthias A HedigerHitoshi Endou
Jul 28, 2007·Clinical Pharmacokinetics·Richard O DayKenneth M Williams
Dec 15, 2010·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Dganit DinourEliezer J Holtzman
May 26, 2012·The American Journal of Medicine·Yanyan ZhuHyon K Choi
Aug 11, 2012·Clinical Journal of the American Society of Nephrology : CJASN·F Perry Wilson, Jeffrey S Berns
Oct 24, 2012·Advances in Chronic Kidney Disease·Ion Alexandru Bobulescu, Orson W Moe
Mar 12, 2013·European Journal of Clinical Pharmacology·Daniel F B WrightNicholas H G Holford
Jan 15, 2014·Current Opinion in Rheumatology·Thomas Bardin, Pascal Richette
Jan 17, 2014·CPT: Pharmacometrics & Systems Pharmacology·N BensonP H van der Graaf
May 21, 2014·Clinical Pharmacology and Therapeutics·J V S Gobburu
Feb 11, 2016·Drugs·Sheridan M Hoy
Apr 24, 2016·Current Rheumatology Reports·David HyndmanJeffrey N Miner

❮ Previous
Next ❯

Citations

Dec 19, 2021·CPT: Pharmacometrics & Systems Pharmacology·Sietse BraakmanHelen Moore

❮ Previous
Next ❯

Methods Mentioned

BETA
urine collection

Clinical Trials Mentioned

NCT01508702

Software Mentioned

R package deSolve
NonMem
R package minpack
R
CentOS
lsoda
. lm

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2022 Meta ULC. All rights reserved