Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers
Michael Gillen,1 Shakti Valdez,2 Dongmei Zhou,2 Bradley Kerr,2 Caroline A Lee,2 Zancong Shen2 1AstraZeneca LP, Gaithersburg, MD, 2Ardea Biosciences, Inc., San Diego, CA, USA Introduction: Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination wi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2016-11-01
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| Series: | Drug Design, Development and Therapy |
| Subjects: | |
| Online Access: | https://www.dovepress.com/effects-of-renal-function-on-pharmacokinetics-and-pharmacodynamics-of--peer-reviewed-article-DDDT |
| _version_ | 1811240639877087232 |
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| author | Gillen M Valdez S Zhou D Kerr B Lee CA Shen Z |
| author_facet | Gillen M Valdez S Zhou D Kerr B Lee CA Shen Z |
| author_sort | Gillen M |
| collection | DOAJ |
| description | Michael Gillen,1 Shakti Valdez,2 Dongmei Zhou,2 Bradley Kerr,2 Caroline A Lee,2 Zancong Shen2 1AstraZeneca LP, Gaithersburg, MD, 2Ardea Biosciences, Inc., San Diego, CA, USA Introduction: Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. Methods: Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60–89 mL/min; N=8), moderate (eCrCl 30–59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data. Results: Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration–time curve by 34%, 54%–65%, and 102%, respectively. Lesinurad plasma Cmax was unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects. Conclusion: Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment. Keywords: lesinurad, pharmacodynamics, pharmacokinetics, renal function, serum urate |
| first_indexed | 2024-04-12T13:23:46Z |
| format | Article |
| id | doaj.art-34b632c22098467f81922ae4bd2aabc4 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-04-12T13:23:46Z |
| publishDate | 2016-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-34b632c22098467f81922ae4bd2aabc42022-12-22T03:31:23ZengDove Medical PressDrug Design, Development and Therapy1177-88812016-11-01Volume 103555356229798Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteersGillen MValdez SZhou DKerr BLee CAShen ZMichael Gillen,1 Shakti Valdez,2 Dongmei Zhou,2 Bradley Kerr,2 Caroline A Lee,2 Zancong Shen2 1AstraZeneca LP, Gaithersburg, MD, 2Ardea Biosciences, Inc., San Diego, CA, USA Introduction: Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. Methods: Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60–89 mL/min; N=8), moderate (eCrCl 30–59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data. Results: Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration–time curve by 34%, 54%–65%, and 102%, respectively. Lesinurad plasma Cmax was unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects. Conclusion: Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment. Keywords: lesinurad, pharmacodynamics, pharmacokinetics, renal function, serum uratehttps://www.dovepress.com/effects-of-renal-function-on-pharmacokinetics-and-pharmacodynamics-of--peer-reviewed-article-DDDTLesinuradpharmacodynamicspharmacokineticsrenal functionserum urate |
| spellingShingle | Gillen M Valdez S Zhou D Kerr B Lee CA Shen Z Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers Drug Design, Development and Therapy Lesinurad pharmacodynamics pharmacokinetics renal function serum urate |
| title | Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers |
| title_full | Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers |
| title_fullStr | Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers |
| title_full_unstemmed | Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers |
| title_short | Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers |
| title_sort | effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers |
| topic | Lesinurad pharmacodynamics pharmacokinetics renal function serum urate |
| url | https://www.dovepress.com/effects-of-renal-function-on-pharmacokinetics-and-pharmacodynamics-of--peer-reviewed-article-DDDT |
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