Background Lesinurad is a novel URAT1 inhibitor that has been well tolerated in humans, with dose-dependent reductions of serum urate (sUA). In vitro experiments and in vivo human absorption, metabolism, and mass balance (AME) studies indicated that hepatic metabolism, renal excretion, and biliary uptake all contributed to the elimination of lesinurad. Drug-drug interaction (DDI) studies with drugs commonly used by gout patients have been conducted. Projections of DDI potential with drugs in different therapeutic areas have also been generated using established preclinical models.
Objectives To evaluate the potential inhibitory effect of lesinurad upon initiation of lesinurad once daily dosing or the potential induction effect of lesinurad following multiple doses of lesinurad on pharmacokinetic (PK) of commonly used drugs such as atorvastatin (OATP1B1 and CYP3A), tolbutamide (CYP2C9 and CYP3A), repaglinide (CYP2C8 and CYP3A), or amlodipine (CYP3A) in healthy subjects, as well as PK and sUA lowering of febuxostat (FBX; CYP2C9) or oxypurinol (URAT1), the active metabolite of allopurinol (ALLO), following once daily (qd) dosing of lesinurad in gout patients with hyperuricemia.
Methods A total of 70 healthy subject volunteers were enrolled across 4 DDI studies with drugs commonly used by gout patients including atorvastatin (N=28), tolbutamide (N=14), repaglinide (N=14), and amlodipine (N=14), given with concurrent administration of first dose or qd doses of lesinurad ranging between 200 and 400 mg. Full PK profiles of these drugs were obtained without coadministration with lesinurad, following first dose, or following at least 10 days of qd doses of lesinurad. A total of 41 gout patients were enrolled across 2 multiple-dose DDI studies with FBX and ALLO. In the ALLO DDI study, patients were administered ALLO 300 mg qd in week 1, a combination of ALLO and lesinurad 400 or 600 mg in week 2, then lesinurad alone in week 3. In the FBX DDI study, patients received FBX 40 or 80 mg qd in week 1, a combination of FBX and lesinurad 400 mg and 600 mg in week 2 and week 3, respectively.
Results In healthy subjects, lesinurad showed minimal inhibitory effects (10-30%) on plasma exposure of atorvastatin, tolbutamide and repaglinide upon first dose of 400 mg lesinurad, the highest dose planned for Phase 3 evaluations. Following 400 mg qd doses of lesinurad, plasma exposure of tolbutamide and repaglinide were unaffected, while plasma exposure of atorvastatin, and amlodipine were minimally decreased. In gout patients, although co-administration of lesinurad 400 mg resulted in 26% decrease in oxypurinol plasma exposure, additive reduction in sUA was observed. Coadminstration of lesinurad 400 mg resulted in minimal (<20%) increases in FBX plasma exposure, and synergistic reductions in sUA. Neither allopurinol nor FBX had any effect on the PK of lesinurad. Preclinical DDI modeling of the most commonly used drugs by gout patients identified few potential interactions
Conclusions Potential drug-drug interactions are limited to mild reductions in oxypurinol (expected due to URAT1 activity) and mild induction of CYP3A4 at the doses being evaluated in Phase 3. No clinically meaningful drug interactions are anticipated with lesinurad
Disclosure of Interest L.-T. Yeh Employee of: Ardea Biosciences, Z. Shen Employee of: Ardea Biosciences, B. Kerr Consultant for: Ardea Biosciences, D. Wilson Employee of: Ardea Biosciences, C. Yang Employee of: Ardea Biosciences, S. Squier Consultant for: Ardea Biosciences, V. Hingorani Consultant for: Ardea Biosciences, D. Hagerty Employee of: Ardea Biosciences, K. Manhard Employee of: Ardea Biosciences, B. Quart Employee of: Ardea Biosciences
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.