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

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 uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure-response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations.

SUBMITTER: Aksenov S

PROVIDER: S-EPMC5828935 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Aksenov Sergey S Peck Carl C CC Eriksson Ulf G UG Stanski Donald R DR

Physiological reports 20180301 5

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 febuxosta ...[more]

PMID: 29488355

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Project description:ObjectivesDiabetes and other metabolic diseases have been linked to the development of periodontitis, but little research has been done to determine whether serum uric acid (SUA) levels and hyperuricemia play a role. This study aimed to investigate the relationship between SUA, hyperuricemia, and periodontitis.MethodsUsing data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, we created a nationally representative data set. We used multivariable logistic regression models to assess the relationship between SUA, hyperuricemia, and periodontitis and presented odds ratios (OR) in women and men, respectively.ResultsIn women, adjusted multivariable regression models showed that SUA (4.1-4.3mg/dl) was associated with higher odds of periodontitis (OR = 1.43; 95% confidence interval (CI):1.0 ~ 2.03, p = 0.047) with SUA (≤ 3.3mg/dl) as reference. The risk of periodontitis tended to increase slightly but insignificantly with increasing SUA levels, and the adverse effects occurred only when SUA increased to a certain level, and then reached a plateau. In men, the adjusted OR values for SUA (4.9-5.2mg/dl), SUA (5.3-5.5mg/dl), SUA (5.9-6.2mg/dl), and SUA (6.3-6.5mg/dl) were 0.66 (95% CI: 0.45 ~ 0.96, p = 0.029), 0.58 (95% CI: 0.40 ~ 0.85, p = 0.006), 0.67(95% CI: 0.47 ~ 0.97, p = 0.035), and 0.67 (95% CI: 0.45 ~ 0.99, p = 0.043), respectively, with SUA (≤ 4.3mg/dl) as reference. The elevated SUA levels are protective against periodontitis, but there is a range within which the risk of periodontitis decreases, followed by a non-significant tendency to increase.ConclusionsThe levels of SUA that are linked to the risk of periodontitis. Future prospective longitudinal studies and strategies are required to further confirm whether controlled SUA treatment is an effective adjunct to systematic periodontal therapy and whether SUA can be used as a diagnostic biomarker to assess the risk or progression of periodontitis.

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Dataset Information

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

Publications

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

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