Asset Details
Do you wish to reserve the book?
POS0935 AR882, A SELECTIVE URAT1 INHIBITOR, EXHIBITS NO DRUG-DRUG INTERACTIONS WITH KEY RENAL, HEPATIC, AND GI TRANSPORTERS
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
POS0935 AR882, A SELECTIVE URAT1 INHIBITOR, EXHIBITS NO DRUG-DRUG INTERACTIONS WITH KEY RENAL, HEPATIC, AND GI TRANSPORTERS
Do you wish to request the book?
POS0935 AR882, A SELECTIVE URAT1 INHIBITOR, EXHIBITS NO DRUG-DRUG INTERACTIONS WITH KEY RENAL, HEPATIC, AND GI TRANSPORTERS
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
POS0935 AR882, A SELECTIVE URAT1 INHIBITOR, EXHIBITS NO DRUG-DRUG INTERACTIONS WITH KEY RENAL, HEPATIC, AND GI TRANSPORTERS
2024
Overview
Background:AR882 is a highly selective URAT1 inhibitor in development for the treatment of gout and tophaceous gout. It has demonstrated favorable pharmacokinetics (PK) and robust efficacy in clinical studies. In AR882 phase 2 studies in patients with gout, no drug interactions (DDIs) were observed between AR882 and the commonly prescribed drugs for comorbidities such as antihyperglycemics, antihypertensives, statins and diuretics. There was no dose adjustment needed for concomitant medications while the efficacy of AR882 was steady. The lack of DDIs with these transporter-mediated drugs is consistent with the results from in vitro modeling and animal studies.Objectives:Comprehensive evaluation of AR882’s DDI potential with key renal, hepatic, and intestinal transporters that are typically associated with drugs used for comorbidity usually seen in gout patients.Methods:In in vitro studies, AR882’s interactions with various transporters were assessed in HEK293 cells expressing MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 and OCT2, or Caco-2 cells/membrane vesicles (P-gp and BCRP, BSEP). Substrate and inhibition assays for relevant transporters were conducted with AR882 in concentrations exceeding clinical drug concentration (i.e., at least 100-fold the Imax,u of high clinical dose at 75 mg). The obtained accumulation ratio (substrate) and the IC50 (inhibition) using model-base methods were analyzed for DDI predication. Furthermore, AR882 potential as a substrate for P-gp and BCRP transporters was assessed using tissue distribution data in rat and renal excretion data from the human ADME study using [14C]AR882. In order to determine the clinical significance of AR882’s DDI potential with BCRP, a phase 1 clinical study dosed in 10 male healthy participants with sulfasalazine 500 mg on Day 1, followed by a second single dose of sulfasalazine 500 mg on Day 4 with multiple-dose of AR882 75 mg administered once daily from Days 4 to 6. Plasma levels of sulfasalazine, as well as metabolites sulfapyridine and mesalamine were determined by LC/MS/MS analyses. PK parameters Cmax, and AUC were assessed to calculate geometric mean ratios.Results:In vitro assessments indicated that AR882 was not a substrate of any key renal and hepatic transporters. AR882 was determined to be a substrate of BCRP and P-gp; AR882 had no inhibitory effect on any transporters except for BCRP with an IC50 of 1.18 µM in animal studies, which warranted a clinical DDI study as an inhibitor of BCRP. Sulfasalazine, a clinical substrate of BCRP and a commonly used drug in autoimmune and rheumatic diseases was selected for the study. Co-administration of AR882 75 mg (maximum therapeutic dose) with sulfasalazine produced no clinically relevant alterations in pharmacokinetics (Cmax and AUC) of sulfasalazine with a geometric mean ratio of 1.09 (co-administration) verse 1.05 (sulfasalazine alone), suggesting no clinically significant BCRP-mediated DDI.Conclusion:AR882 has been comprehensively evaluated for transporter-mediated DDI potential in vitro and in clinical studies, and exhibited no DDI concerns. These findings demonstrated that AR882 can be safely given in gout patients with various comorbid conditions including diabetes, hypertension and hyperlipidemia and the concomitant medications that are primarily cleared via transporters.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Zancong Shen Arthrosi Therapeutics Inc, Rongzi Yan Arthrosi Therapeutics Inc, Elizabeth Polvent Arthrosi Therapeutics Inc, Vijay Hingorani Arthrosi Therapeutics Inc, Shunqi Yan Arthrosi Therapeutics Inc, Robert Keenan Arthrosi Therapeutics Inc, Li-Tain Yeh Arthrosi Therapeutics Inc.
