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Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males.

Shen Z, Rowlings C, Kerr B, Hingorani V, Manhard K, Quart B, Yeh LT, Storgard C - Drug Des Devel Ther (2015)

Bottom Line: Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing.A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules.Lesinurad was generally safe and well tolerated.

View Article: PubMed Central - PubMed

Affiliation: Ardea Biosciences, Inc. (a member of the AstraZeneca group), San Diego, CA, USA.

ABSTRACT
Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.

No MeSH data available.


Related in: MedlinePlus

Dose linearity and proportionality of lesinurad under fasted (5–400 mg) or fed (100–600 mg) conditions in healthy subjects (A), and correlation between plasma lesinurad exposure or amount excreted in urine and serum uric acid-lowering effect (B).Abbreviations: AUC, area under the plasma concentration–time curve; CI, confidence interval; Cmax, maximum observed plasma concentration.
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f4-dddt-9-3423: Dose linearity and proportionality of lesinurad under fasted (5–400 mg) or fed (100–600 mg) conditions in healthy subjects (A), and correlation between plasma lesinurad exposure or amount excreted in urine and serum uric acid-lowering effect (B).Abbreviations: AUC, area under the plasma concentration–time curve; CI, confidence interval; Cmax, maximum observed plasma concentration.

Mentions: The dose proportionality of lesinurad exposure (Cmax and AUC) following a single oral dose on day 1 was assessed by pooling all available data from the three studies. As shown in Figure 4A, both Cmax and AUC exposures showed a dose-proportional increase at doses of 5 to 400 mg under fasted conditions with power model slope b wholly within the 0.8 to 1.25 interval. Under fed conditions, the increase in lesinurad Cmax and AUC was considered dose proportional at doses of 100 to 600 mg despite the slope b (1.13, 95% CI: 1.00–1.26) for AUC being marginally outside the 0.8 to 1.25 interval, likely due to small group size and variability between studies, subjects, and formulation. Dose proportionality was not explored in multiple doses due to the narrow dose range evaluated in the fed condition.


Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males.

Shen Z, Rowlings C, Kerr B, Hingorani V, Manhard K, Quart B, Yeh LT, Storgard C - Drug Des Devel Ther (2015)

Dose linearity and proportionality of lesinurad under fasted (5–400 mg) or fed (100–600 mg) conditions in healthy subjects (A), and correlation between plasma lesinurad exposure or amount excreted in urine and serum uric acid-lowering effect (B).Abbreviations: AUC, area under the plasma concentration–time curve; CI, confidence interval; Cmax, maximum observed plasma concentration.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494180&req=5

f4-dddt-9-3423: Dose linearity and proportionality of lesinurad under fasted (5–400 mg) or fed (100–600 mg) conditions in healthy subjects (A), and correlation between plasma lesinurad exposure or amount excreted in urine and serum uric acid-lowering effect (B).Abbreviations: AUC, area under the plasma concentration–time curve; CI, confidence interval; Cmax, maximum observed plasma concentration.
Mentions: The dose proportionality of lesinurad exposure (Cmax and AUC) following a single oral dose on day 1 was assessed by pooling all available data from the three studies. As shown in Figure 4A, both Cmax and AUC exposures showed a dose-proportional increase at doses of 5 to 400 mg under fasted conditions with power model slope b wholly within the 0.8 to 1.25 interval. Under fed conditions, the increase in lesinurad Cmax and AUC was considered dose proportional at doses of 100 to 600 mg despite the slope b (1.13, 95% CI: 1.00–1.26) for AUC being marginally outside the 0.8 to 1.25 interval, likely due to small group size and variability between studies, subjects, and formulation. Dose proportionality was not explored in multiple doses due to the narrow dose range evaluated in the fed condition.

Bottom Line: Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing.A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules.Lesinurad was generally safe and well tolerated.

View Article: PubMed Central - PubMed

Affiliation: Ardea Biosciences, Inc. (a member of the AstraZeneca group), San Diego, CA, USA.

ABSTRACT
Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.

No MeSH data available.


Related in: MedlinePlus