Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males
| Autor: | Colin Edward Rowlings, Vijay Hingorani, Kimberly Manhard, C. Storgard, Zancong Shen, Brad Kerr, Li-Tain Yeh, Barry D. Quart |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Adolescent Organic Cation Transport Proteins Pharmaceutical Science Administration Oral Biological Availability Organic Anion Transporters urinary excretion Capsules clearance Pharmacology chemistry.chemical_compound Young Adult Pharmacokinetics Double-Blind Method Uricosuric Agent Drug Discovery medicine food effect Humans single and multiple doses Dosing urate lowering Original Research Drug Design Development and Therapy Cross-Over Studies Lesinurad Triazoles Uricosuric Agents medicine.disease Crossover study Healthy Volunteers Gout Uric Acid Pharmaceutical Solutions Renal Elimination chemistry Gastrointestinal Absorption Pharmacodynamics Thioglycolates Uric acid URAT1 |
| Zdroj: | Drug Design, Development and Therapy |
| ISSN: | 1177-8881 |
| Popis: | Zancong Shen, Colin Rowlings, Brad Kerr, Vijay Hingorani, Kimberly Manhard, Barry Quart, Li-Tain Yeh, Chris Storgard 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. Arelative 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. Keywords: urinary excretion, urate lowering, URAT1, single and multiple doses, food effect, clearance |
| Databáze: | OpenAIRE |
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