title: Evaluation of Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption Inhibitor, and CYP Enzyme Substrates Sildenafil, Amlodipine, Tolbutamide, and Repaglinide.
abstract: Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of lesinurad, clinical drug interaction studies were conducted. Open-label studies in volunteers investigated the effects of single-/multiple-dose lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction). There was no apparent induction of CYP2C8 and CYP2C9 following repeated lesinurad administration, although no inhibition of CYP2C9 and modest inhibition of CYP2C8 were observed following single-dose lesinurad. Consistent with in vitro observations, lesinurad (200 mg once daily) was an inducer of CYP3A based on the effects on sildenafil exposure. Sildenafil exposure decreased by approximately 34% for Cmaxand AUC when administered with multiple-dose lesinurad 200 mg and allopurinol 300 mg, relative to sildenafil alone. During lesinurad therapy, the possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy monitored because of induction of CYP3A by lesinurad.
authors.affiliation: AstraZeneca LP, Gaithersburg, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wilson
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Shakti
authors.initials: S
authors.lastname: Valdez
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lee
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Ardea Biosciences, Inc., San Diego, CA, USA.
authors.forename: Zancong
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000328:Adult; D017311:Amlodipine / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000493:pharmacokinetics*; D000068677:Sildenafil Citrate / Q000493:pharmacokinetics*; D013864:Thioglycolates / Q000008:administration & dosage* / Q000494:pharmacology; D014044:Tolbutamide / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D002219:Carbamates; D010880:Piperidines; D013864:Thioglycolates; D014230:Triazoles; C000593471:lesinurad; D017311:Amlodipine; C072379:repaglinide; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D000068677:Sildenafil Citrate
keywords: CYP enzyme substrates; gout; lesinurad; pharmacokinetics