BackgroundChronic gout is a significant clinical problem in Asia, including Japan, where many patients remain suboptimally treated with currently available therapies. Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia.ObjectivesThe aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy Japanese and non-Asian adult male subjects.MethodsThis was a Phase 1, randomized, single-blind, placebo-controlled study (NCT01872832). Panels of 8 Japanese male subjects were randomized in a 3:1 ratio to receive a modified-release formulation of oral verinurad (2.5 mg, 5 mg, 10 mg, 15 mg) or placebo administered as a single dose in a fasted state and as multiple once-daily doses in a fed state for 7 days. A panel of 8 non-Asian male subjects received single and multiple doses of oral verinurad (10 mg) or placebo. Serial plasma/serum and urine samples were assayed for verinurad and uric acid at predetermined time points. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs).ResultsOf 48 randomized subjects, 46 (Japanese: 39, non-Asian: 7) completed the study. Treatment groups were generally well balanced; however, mean body weight and body mass index were approximately 14% and 7% lower, respectively, in Japanese than non-Asian subjects. Following single- or multiple-oral doses of verinurad in Japanese subjects, exposure (maximum plasma concentration [Cmax] and area under the plasma concentration-time curve [AUC]) increased in a near dose-proportional manner under fasted or fed conditions. The time to Cmax (Tmax) was approximately 1.25–2.0 hours post-dose under fasted conditions. A moderate-fat meal delayed Tmax up to 5 hours post-dose and increased plasma verinurad exposures up to 109%. Following once-daily multiple doses, there was modest accumulation of verinurad. Cmax and AUC were 38% and 23% higher, respectively, in Japanese versus non-Asian subjects, largely due to the difference in body weight. Mean reductions in serum uric acid following once-daily multiple dosing of verinurad 10 mg were 62% and 58% at maximum reduction and 46% and 44% at 24 hours post-dose in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses. One Japanese subject discontinued verinurad due to an AE of urticaria that resolved after 11 days. No serious AEs, Grade 3 or 4 AEs, or clinically significant laboratory or ECG abnormalities were noted.ConclusionsVerinurad significantly lowered serum uric acid and was well tolerated in both healthy Japanese and non-Asian males, despite small differences in plasma pharmacokinetics. These data support further evaluation of once-daily verinurad as a treatment for hyperuricemia with or without gout in the Japanese population.AcknowledgementsThe authors thank Caroline Lee and Zancong Shen of Ardea Biosciences, Inc., for critical review of the abstract.Disclosure of Interest...
BackgroundVerinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for the treatment of gout and asymptomatic hyperuricemia.ObjectivesThis Phase 2a, randomized, open-label, multicenter study investigated the multiple-dose pharmacodynamics (PD), pharmacokinetics (PK), and safety of oral verinurad in combination with allopurinol versus allopurinol alone in adults with gout (NCT02498652).MethodsPatients aged ≥18 and ≤75 years with gout and serum uric acid (sUA) ≥8 mg/dL were randomized to 1 of 2 cohorts to receive allopurinol (300 mg) in combination with verinurad (dose range 2.5 mg to 20 mg) and allopurinol 300 mg or 600 mg alone (each treatment period was 7 days). Medications were administered once daily ∼30 min after breakfast (for allopurinol 300 mg b.i.d. group, the second allopurinol dose was in the evening). Colchicine 0.6 mg for gout flare prophylaxis was initiated at approximately Day -14 (start of urate-lowering therapy [ULT]) washout) or Day -7 if not on ULT. Serial blood and urine samples were measured on Days -1, 1, 7, 14, 21, 28, and 35 for PD and PK endpoints. Safety assessments included adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters.ResultsForty-one patients were randomized (n=20–21 per cohort). Serum PD data pooled across cohorts demonstrated maximal % decrease in sUA from baseline (Emax)at 6–10 h after verinurad and allopurinol combination treatment. Addition of verinurad (2.5 mg to 20 mg) to allopurinol decreased sUA in dose-dependent manner (Figure). Greater sUA reductions were observed for dose combinations of verinurad ≥5 mg with allopurinol 300 mg versus allopurinol 600 mg alone, while allopurinol 600 mg once daily was equivalent to allopurinol 300 b.i.d. Emax was 46.9%, 58.9%, 59.9%, 67.1%, 68.4%, and 74.3% for verinurad at doses of 2.5, 5, 7.5, 10, 15, and 20 mg in combination with allopurinol 300 mg, versus 39.7%, 53.8%, and 54.4% with allopurinol 300 mg, allopurinol 600 mg, and allopurinol 300 mg b.i.d. alone. No drug-drug interaction on verinurad and allopurinol plasma PK parameters was observed.ConclusionsVerinurad coadministered with allopurinol dose-dependently decreased sUA. All dose combinations of verinurad and allopurinol in this study were generally well tolerated with no serious AEs or renal-related events during combination treatment.Disclosure of InterestR. Fleischmann Grant/research support from: Ardea Biosciences, Inc., P. Winkle Employee of: Anaheim Clinical Trials, J. Miner Employee of: Ardea Biosciences, Inc., X. Yan Employee of: Ardea Biosciences, Inc., L. Hicks Employee of: Ardea Biosciences, Inc., S. Valdez Employee of: Ardea Biosciences, Inc., J. Hall Employee of: Ardea Biosciences, Inc., M. Hernandez-Illas: None declared
BackgroundA key factor in the success of gout management is the long-term lowering of uricemia below predetermined targets (300 or 360μ mol/l). Monitoring of uricemia in gout patients is therefore important, and is presently done in the laboratory on plasma samples obtained after venous puncture. An accurate uric acid (UA) meter allowing rapid testing by the health care professionals and self-measurement by the patient should improve management of gout.ObjectivesThis study aimed to assess the reliability of immediate UA measurement in capillary blood samples obtained from fingertip puncture using the HumaSensPlus point-of-care meter (meter) compared with that of a standard laboratory assay (lab).MethodsCapillary UA levels were measured from 236 consenting diabetic patients using the commercially available HumaSensPlus UA meter (European Conformity marked and approved for EU market use). Each patient also had a plasma UA measurement in the biochemistry laboratory using an uricase automated colorimetric assay. Since the UA meter has a dynamic range of 180–1190μ mol/l, when the values were out-ranged (meter reading LO or HI), they were individually compared to corresponding plasma measurements. Agreement between capillary and plasma UA levels was assessed by Intraclass Correlation Coefficient (ICC) and Bland-Altman graphic representation. Best capillary UA threshold for detection of hyperuricemia (plasma UA>360μmol/l) was determined from a ROC curve, relationship between methods were identified by regression. Impact of potential confounding factors (biological parameters/treatments) was searched. A total of 206 paired measurements were required for estimation of an ICC of 0.80 with a precision of 0.10 at alpha risk of 0.05%. To better understand discrepancies between meter and lab, results were compared to reference plasma UA measurements by liquid chromatography-mass spectrometry (LC-MS) in a subgroup of 77 patients who gave complementary consent.ResultsFourteen capillary samples were read LO by the meter: 11 were confirmed by lab to be below 180μmol/l and 3 were above (189, 206 and 428μmol/l). Two capillary samples were read HI and were measured at 303 and 213μmol/l by lab. In the remaining 222 samples with meter and lab values, ICC was 0.90 [0.87–0.92] and Bland-Altman curve showed acceptable agreement over all the tested values. Best meter threshold for detection of hyperuricemia by the HumaSensPlus meter was 330μmol/l (sensitivity 0.89, specificity 0.89, area under the ROC curve 0.95). Based on regression, plasma uricase of 360μmol/l corresponded to 343μmol/l. Among the biological parameters tested, only hematocrit impacted capillary uric acid measurements, however negligibly. No medication appeared to significantly affect test results. Plasma uricase measurements were better correlated to LC-MS measurements (r=0.98 [0.96–0.99]) than capillary measurements (r=0.84 [0.75–0.90]).ConclusionsResults of the HumaSensPlus meter were reasonably comparable to those of the laboratory assay. It is easy to use and may be us...
BackgroundApproximately 70% of urate is excreted by the kidney. Renal excretion is governed by reabsorption and secretion in the proximal convoluted tubule. However, there is little direct evidence that renal uric acid secretion occurs in humans, and it is unknown if higher renal uric acid reabsorption or low renal uric acid secretion contributes to the low fractional excretion of uric acid (FEUA) observed in patients with gout.ObjectivesThe objectives of the study were to test the hypothesis that uric acid secretion occurs in humans, to distinguish uric acid secretion from incomplete reabsorption, and to determine if insufficient secretion and/or enhanced reabsorption are responsible for low FEUA.MethodsPatients with gout in a Phase II study were treated once daily with 40 and 80 mg of febuxostat (FBX), with each treatment lasting 1 week. FBX is a xanthine oxidase inhibitor that reduces uric acid production and lowers serum uric acid (sUA). sUA and FEUA were measured at baseline and at the end of each treatment. sUA (X-axis) and FEUA (Y-axis) were plotted to evaluate the kinetics of renal uric acid handling (Figure).ResultsForty-five male patients with gout, with a mean (SD) age of 49±9.3 years and BMI of 32±3.9 kg/m2, participated in this study. As has been observed in previous publications, decreasing sUA led to a decrease in FEUA. However, this effect reached a plateau at low sUA levels for those who had low (<3.5%) baseline FEUA; the FEUA did not decrease further when the FBX dosage was increased from 40 mg to 80 mg (Figure). The FEUA response to decreasing sUA reaches a plateau at an FEUA of ∼ 2.5%. In contrast, the curve for fractional excretion of glucose reaches zero at lower plasma glucose levels.1 Since a prominent difference in renal handling of uric acid and glucose is that glucose is not secreted while uric acid is believed to be secreted, we suggest that the plateauing of the FEUA curve at the lower sUA range is due to renal uric acid secretion. Preliminary modeling of transporter kinetics also suggests that the observed relationship between sUA and FEUA requires secretion. In addition, the sUA level at which the FEUA begins to rise (equivalent to the renal glucose threshold) is higher for those whose baseline FEUA was low, and this observation is consistent with the hypothesis that patients with gout with low FEUA have higher reabsorption capacity. To determine the ultimate contribution of secretion to low FEUA, sUA will need to be lowered even further.ConclusionsWe provide direct evidence for renal uric acid secretion occurring in humans. This method can also be used to determine the relative importance of candidate renal secretory transporters in the secretion of uric acid. Higher reabsorption capacity appears to contribute to low baseline FEUA.ReferencesDeFronzo RA, et al. Diabetes Care. 2013;36:3169–3176.AcknowledgementResearch sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca.Disclosure of InterestS. Liu Employee of: Ardea Bioscienc...
BackgroundLifestyle intervention is an important component in uricemic control. Diets with low purine and fructose content, as well as limited alcohol consumption, are recommended for people with hyperuricemia/gout.1 It has been reported that a 2-day fast can lead to higher serum uric acid (sUA) levels, with a concomitant decrease in urinary uric acid excretion.2 This work explores whether a shorter fast, such as simply skipping breakfast, affects sUA levels.ObjectivesTo study the effect on sUA of skipping breakfast.MethodsTwo successive experiments were conducted with the same group of healthy subjects (N=30). In the first experiment the subjects consumed all three meals during the day, whereas in the second experiment the subjects did not eat breakfast but had the other two meals as usual. sUA and fractional excretion of uric acid (FEUA) were measured throughout the 24 hr experiment period. In addition, corresponding sUA levels were simulated based on the measured FEUA in order to evaluate the contribution of FEUA to the effects of breakfast on measured sUA.ResultsAt 6, 12 and 24 hr after breakfast (∼8 am), the mean±SE change from baseline (pre-breakfast) in sUA was -0.3±0.09, -0.4±0.1 and +0.1±0.09 mg/dL, respectively, when the group ate breakfast (Figure). These changes average to a decrease in sUA of 0.2±0.08 mg/dL over 24 hrs. In comparison, the change in sUA from baseline was +0.3±0.05, +0.1±0.09 and +0.3±0.07 mg/dL at 6, 12 and 24 hr when they did not eat breakfast. These changes average to an elevation in sUA of 0.2±0.05 mg/dL over 24 hrs. As a result, the difference in sUA (no breakfast - breakfast) was +0.4±0.09 mg/dL (p<0.0001). In the first 6 hrs after breakfast, FEUA were 7.3±0.45 with breakfast and 5.7±0.33 without breakfast (Figure, p<0.01). However, when sUA levels are simulated based on the observed FEUA, the difference in FEUA between breakfast and no breakfast cannot fully explain the difference in their observed sUA.ConclusionsSkipping breakfast leads to a 0.4 mg/dL elevation in sUA over 24 hr. A decreased FEUA is partially responsible for the difference in sUA; however, there are likely other mechanisms involved as well. Routinely skipping breakfast might lead to even higher elevations in sUA.ReferencesKhanna D et al. Arthritis Care Res (Hoboken). 2012;64:1431–1446.Maclachlan MJ and Rodnan GP. Am J Med. 1967;42:38–57.AcknowledgementResearch sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca.Disclosure of InterestS. Liu Employee of: Ardea Biosciences, Inc., J. Miner Employee of: Ardea Biosciences, Inc.
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