Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


The Combination of Tranilast with Allopurinol Results in Enhanced Urate Lowering.

Sundy4,  John S., Kitt5,  Michael M., Griffith1,  Sue G., Stoltz2,  Randall R., Goldblum3,  Ronald

ClinPharma Resources, San Diego, CA
Covance, Evansville, IN
CPC Inc, Carlsbad, CA
Duke University Medical Center, Durham, NC
Nuon Therapeutics, Inc., San Mateo, CA

Background:

Reduction of serum urate (sUA) can be achieved with uricosuric drugs, which enhance excretion of uric acid, or with inhibitors of xanthine-oxidase, which interrupt the enzymatic cascade converting xanthine to urate. Combination therapy utilizing both mechanisms may be useful in producing lower sUA levels and higher responder rates than a single mechanism in patients with hyperuricemia and gout.

Study Design:

A double-blind, 5-treatment period, crossover Phase 2 study evaluated co-administration of tranilast and allopurinol in patients with hyperuricemia. Subjects were randomized 1:1:1 in an initial 3-treatment crossover phase to 300 mg tranilast (T300), 300 mg allopurinol (A300), or a combination of A300+ T300 (C300). At end of the third period, patients were randomized 1:1 in a 2-treatment crossover phase of allopurinol 400 mg (A400) or a combination of A400+ T300 (C400). Each period within a phase was 14 days in duration with 7 days treatment orally once daily (Days 1–7), followed by a 7-day washout interval. sUA levels were obtained each day of dosing and 24 hours after last dose. Plasma concentrations of tranilast, allopurinol, and oxypurinol (allopurinol's active metabolite) were evaluated over the 24-hour interval after last dose of each 7-day period. The primary objective was to compare % change from baseline sUA of the combination with tranilast or allopurinol alone.

Results:

Twenty male patients were enrolled with mean age 43 years, BMI 29.7 kg/m2, and baseline sUA 8.1 mg/dL. Combination treatment resulted in greater percentage decrease in sUA than tranilast or allopurinol alone (see table). With C400, 61% of patients achieved sUA levels <4.0 mg/dL, which was significantly greater than the 11% achieved with C300 or A400 alone (p=0.0027).

 T300 N=19A300 N=19C300 (T300+ A300) N=18A300 N=19C300 (T300+ A300) N=18
Mean % sUA Change from Baselinea-14%-35%-43%b-38%-49%c
Responders <6 mg/mL sUA28%94%100%94%100%
Responders <4 mg/mL sUA0%6%11%11%61%
a24 h after Day 7 dosebP-value for LSMean difference between T300 or A300 and C300; <=0.0002.cP-value for LSMean difference between A300 and C300; <=0.0001.

Coadministration of allopurinol with tranilast did not affect plasma tranilast Cmax or AUC. Although tranilast had no effect on plasma allopurinol pharmacokinetics, tranilast decreased plasma oxypurinol Cmax and AUC by ~25–30%, which was an expected interaction, as uricosurics such as tranilast inhibit the reabsorption of both uric acid and oxypurinol in the renal tubules. All treatment regimens were well-tolerated.

Conclusion:

In patients with hyperuricemia, combining tranilast 300 mg with allopurinol 400 mg is more effective in reducing sUA to normal levels than allopurinol alone.

To cite this abstract, please use the following information:
Sundy, John S., Kitt, Michael M., Griffith, Sue G., Stoltz, Randall R., Goldblum, Ronald; The Combination of Tranilast with Allopurinol Results in Enhanced Urate Lowering. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :160
DOI: 10.1002/art.27929

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