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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

Plasma lesinurad concentration profiles. (A) and median percent change from baseline in serum uric acid profiles following single doses of lesinurad in healthy male subjects (B).Notes: The points before “0” represent the pre-dose values for all groups.
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f1-dddt-9-3423: Plasma lesinurad concentration profiles. (A) and median percent change from baseline in serum uric acid profiles following single doses of lesinurad in healthy male subjects (B).Notes: The points before “0” represent the pre-dose values for all groups.

Mentions: The median plasma concentration–time profiles for healthy subjects administered lesinurad oral solution at single doses ranging from 5 mg to 600 mg under fasted or fed conditions is shown in Figure 1A. Lesinurad was rapidly absorbed, with a median Tmax of 0.25 to 1.5 hours (Table 1). Mean estimated terminal t1/2 ranged from 2.7 to 12.7 hours, with the exception of 34.6 hours observed for the 100 mg group with food. This outlier value is likely attributed to individual subjects with anomalously higher concentrations in the terminal phase that led to greater calculated terminal half-lives. Total oral clearance of lesinurad ranged from 92 to 149 mL/min, indicating that lesinurad is a low clearance drug (compared with hepatic blood flow as high as 1.0–1.5 L/min). In urine, unchanged drug ranged from 18.9% to 31.7% (overall, 23.4%) of dose, while renal clearance ranged from 19.8 to 47.7 mL/min (overall, 27.5 mL/min).


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)

Plasma lesinurad concentration profiles. (A) and median percent change from baseline in serum uric acid profiles following single doses of lesinurad in healthy male subjects (B).Notes: The points before “0” represent the pre-dose values for all groups.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-3423: Plasma lesinurad concentration profiles. (A) and median percent change from baseline in serum uric acid profiles following single doses of lesinurad in healthy male subjects (B).Notes: The points before “0” represent the pre-dose values for all groups.
Mentions: The median plasma concentration–time profiles for healthy subjects administered lesinurad oral solution at single doses ranging from 5 mg to 600 mg under fasted or fed conditions is shown in Figure 1A. Lesinurad was rapidly absorbed, with a median Tmax of 0.25 to 1.5 hours (Table 1). Mean estimated terminal t1/2 ranged from 2.7 to 12.7 hours, with the exception of 34.6 hours observed for the 100 mg group with food. This outlier value is likely attributed to individual subjects with anomalously higher concentrations in the terminal phase that led to greater calculated terminal half-lives. Total oral clearance of lesinurad ranged from 92 to 149 mL/min, indicating that lesinurad is a low clearance drug (compared with hepatic blood flow as high as 1.0–1.5 L/min). In urine, unchanged drug ranged from 18.9% to 31.7% (overall, 23.4%) of dose, while renal clearance ranged from 19.8 to 47.7 mL/min (overall, 27.5 mL/min).

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