Uric Acid Lowering Effect of Allopurinol in Minnesota Hmong Adults

Uric Acid Lowering Effect of Allopurinol in Minnesota Hmong Adults with Hyperuricemia or Gout
Youssef M. Roman, Pharm.D.1, Kathleen A. Culhane-Pera, M.D.,M.A.2, Shoua Yang, B.S.2, John Yang, B.S.2, Muaj C. Lo, M.D.2, Robert J. Straka, Pharm.D.1
and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN,2 West Side Community Health Services, St. Paul, MN
Introduction
Table 2. Key Uric Acid Parameters Pre and Post Allopurinol Therapy (N=31)
 Hyperuricemia (HU), (Serum Uric Acid [SUA] > 6mg/dL) is the strongest predictor for developing gout
and highly associated with cardiovascular diseases(1)
 The Hmong, a unique Asian population of 64,000 in Minnesota, have a 2-5 fold increased risk of gout
and gout associated co-morbidities compared to non-Hmong in Minnesota(2,3)
 Allopurinol is a purine analog xanthine oxidase inhibitor used to lower uric acid production
 Hmong patients with gout perceive allopurinol to be ineffective, contributing to poor adherence rate(4)
 Central Research Question: Does allopurinol have a low efficacy, or does poor adherence account
for perceived ineffectiveness in Hmong patients with gout?
 AIM 1: Quantify the uric acid (UA) lowering effect of allopurinol in Hmong
 AIM 2: Characterize UA disposition parameters pre and post allopurinol therapy in Hmong
 Significance: Elucidation of factors contributing to the perceived lack of efficacy can help improve the
management gout in Hmong patients.
Parameter
Time
Urine UAex Rate (mg/min)
Mean + (SD)
CLR (UA) (mL/min)
Mean + (SD)
% FEUA
Mean + (SD)
Urine Spot ( UUA /Ucr)
Mean + (SD)
Exclusion
1- no visit show
1- study drop-out
1- skin rash AE
Fig. 1
Visit 2 (V2)
N=35
7.04 (2.6)
6.25 (2.0)
0.09
6.39 (3.6)
4.88 (2.2)
<0.001
0.53 (0.16)
0.28 (0.13)
<0.001
1.4
6
4
V1 (n=54)
V2 (n=35)
1.2
1.0
0.8
0.6
0.2
0
0.0
V(2)0hr
V(2)6hr
V(3)0hr
V(3)6hr
V2 UUAex
V3 UUAex
CrCl Pre and Post Allopurinol
%FEUA(0-6)hr Pre and Post Allopurinol
160
20
Fig. 5
Fig. 4
140
V3 (n=32)
16
49 ± 13.6
45 ± 12.7
43 ± 12.6
Male (Count, %)
48 (89%)
31 (89%)
29 (91%)
BMI (kg/m2)
31.5 ± 5.4
32.4 ± 5.5
33.4 ± 5.9
Waist Circumference
(inches)
39.9 ± 5.0
40.6 ± 5.2
39.9 ±3.0
Systolic BP (mm Hg)
146 ± 20
142 ± 21
143 ± 20
Diastolic BP (mm Hg)
90 ± 11
88 ± 13
92 ± 11
SUA (mg/dL)
8.3 ± 2.1
9.3 ± 1.6
5.5 ± 2.1
146 ± 92
145 ± 67
118 ± 59
eGFR (ml/min)
57 ± 23
62 ± 21
91 ± 29
54 Hmong participants were enrolled at V1 with 32 completing V3 (Table 1)
1 participant was excluded from the final analyses due to poor compliance
31 participants (90% males) were analyzed, had a mean (+SD)% adherence rate of 93 (+7)%
Allopurinol reduced SUA from 9.4 to 5.5 mg/dL (p<0.001) with mean (+SD) % reduction of 40
(+11)% (Fig. 2) and UUAex rate from 0.65 to 0.36 (mg/min) (P <0.001) (Fig. 3)
 Allopurinol reduced %FEUA(0-6hr) from 6.4 to 4.9% (P <0.001) (Fig. 4), Urine(UA)/Urine(Cr)(0-6hr)
from 0.53 to 0.28 (P <0.001) , CLR(UA)(0-6hr) from 7.04 to 6.25 mL/min (p=0.09) (Table 2)
 Using Cockcroft - Gault method, allopurinol increased eGFR from 65 to 91 ml/min (p<0.001)
(Fig. 5)
 Allopurinol increased CL(R)(Cr)(0-6hr) from 125 to 141 ml/min (p= 0.186)
 Allopurinol effectively reduced SUA in Hmong with
a mean of 40 (+11)% range [23-60%]
 The disposition of of UA as measured by pre
allopurinol Urine UAex rate and %FEUA suggest the
Hmong are more likely to be overproducers of UA
rather than underexcreters (Fig. 6)
Interpretations
 Given the magnitude of SUA reduction (40%), high
adherence rate (93%), and overproducer
classification, allopurinol appears to be generally
effective in the Hmong compared to other
populations(5)
 Marked inter-subject variability of % SUA reduction
was noted
 The Hmong have a higher CLR(UA) and CLR(Cr) preand post-allopurinol compared to other
populations(5,6)
 Given the high inter-subject variability of response
to allopurinol, exploration of other sources of
variations (e.g. genetics) are warranted
 Prospective exploration of pharmacogenetic-based
sources of variability are planned with a focus on
UA transporters and metabolizing enzymes as are
comparative efficacy studies of urate lowering
therapies considering diet
120
14
12
10
8
6
Glucose (mg/dL)
Conclusions
Future Directions
0.4
2
Visit(1)
UUAex (0-6)hr Rate Pre and Post Allopurinol
Fig. 3
UUAex Rate (mg/min)
Serum Uric Acid (mg/dL)
8
18
Results




<0.001
10
Disclosure
100
All authors have declared no conflict of interests
80
Acknowledgments
60
4
40
2
0
20
V2% FEUA(0-6)hr
Visit 3 (V3)
N=32
0.36 (0.13)
12
% FEUA
Exclusion
2- CrCl<30 ml/min
17- did not meet
other criteria, no
longer interested
or lost to contact
Visit 1 (V1)
N=54
0.65 (0.21)
Fig. 2
Table 1. Participants Characteristics by Study Visit
Characteristics count
(%) or mean + (SD)
Age (years)
(0-6)hr
14
 Prospective open-label clinical trial (NCT02371421)
 Hmong participants ≥ 18 years old with CrCl >30ml/min, SUA ≥ 6mg/dL or documented use of UA
lowering drugs and both parents are Hmong (Fig. 1)
 After baseline visit (V1), participants underwent 7-10 days washout of UA lowering drugs, if applicable
 Allopurinol was dosed for 7 days as 100mg twice daily followed by 7 days of 150mg twice daily
 Tablet counts were used to quantify adherence
 Change in SUA, UA renal clearance (CLR(UA)), Urinary UA excretion (UUAex) rate and % UA fractional
excretion (%FEUA) at 0, 2, 4 and 6 hours, were used to determine hyperuricemia classification
(Fig. 8) (overproducers vs. underexcreters) and response to allopurinol
 Pre (V2) and post (V3) allopurinol measurements were compared using a paired t-test with p<0.05 for
statistical significance
P-value
(0-6)hr
SUA Changes Pre and Post Allopurinol Therapy
Methods
~ 200 subjects
evaluated for
inclusion
Pre-Allopurinol (V2) Post-Allopurinol (V3)
eGFR (ml/min)
1Experimental
V3% FEUA(0-6)hr
N=2
Underexcreter
V2 (CrCl)
N=15
Combined
V3 (CrCl)
N=14
Overproducer
Fig. 6
UUAex ≤ 25 mg/hr
FEUA < 5.5%
UUE > 25 mg/hr
FEUA < 5.5%
UUAex > 25 mg/hr
FEUA ≥ 5.5%
Criteria used to classify participants’ hyperuricemia pre-allopurinol (V2)
 Hmong Gout Research Board, West Side Community Health Services.
 University of Minnesota , Office of Community Engagement of the Clinical
and Translational Science Institute, 2014 Collaborative Pilot Grants CTSI No.
22556
 Research reported in this publication was supported by the National Center
for Advancing Translational Sciences of the National Institutes of Health
Award Number UL1TR000114. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National
Institutes of Health.
 Program in Health Disparity Research Trainee Travel Award
References
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(2004): 853-857
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