Individualized treatment strategies for hyperuricemia
informed by a semi-mechanistic exposure-response model
of uric acid dynamics
, Carl C. Peck
, Ulf G. Eriksson
& Donald R. Stanski
1 Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Waltham, MA
2 University of California at San Francisco and NDA Partners LLC, San Luis Obispo, CA
3 Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
4 Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gaithersburg, MD
Allopurinol, febuxostat, fractional excretion,
glomerular ﬁltration rate, gout,
hyperuricemia, lesinurad, mathematical
modeling, nephrolithiasis, oxypurinol,
pharmacodynamics, pharmacokinetics, renal
physiology, uric acid, uricosuria, uricosuric,
xanthine oxidase inhibitor.
Sergey Aksenov, AstraZeneca, 35 Gatehouse
Dr, Waltham, MA 02451.
No funding information provided.
Received: 6 December 2017; Revised: 18
January 2018; Accepted: 19 January 2018
Physiol Rep, 6 (5), 2018, e13614,
To provide insight into pharmacological treatment of hyperuricemia we devel-
oped 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 oxi-
dase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the
selective UA reabsorption inhibitor lesinurad, approved for use in combina-
tion 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 excre-
tion 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 uptitra-
tion 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.
Hyperuricemia is an abnormally elevated concentration of
uric acid in serum that is associated with increased risk of
gout, and independently of renal and cardiovascular dis-
ease (Bardin and Richette 2014). Uric acid production is
a consequence of purine degradation. While the physio-
logical processes of uric acid disposition have been exper-
imentally identiﬁed, their roles in the hyperuricemic state
and effects of pharmacological treatment have not been
previously quantitatively described.
Pathophysiological and molecular abnormalities in the
processes that contribute to production and elimination
of uric acid in the body are well studied and understood.
Mutations have been identiﬁed that alter activity of
enzymes involved in purine metabolism and result in
pathological overproduction of uric acid (Seegmiller et al.
1967; Sperling et al. 1973). Overwhelming release of
ª 2018 Astra Zeneca. Physiological Reports published by Wiley Periodicals, Inc. on behalf of
The Physiological Society and the American Physiological Society
This is an open access article under the terms of the Creative Commons Attribution License,
which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
2018 | Vol. 6 | Iss. 5 | e13614
Physiological Reports ISSN 2051-817X