Abstract: SA-PO635
Sparsentan Pharmacokinetics and Pharmacodynamics as the Basis of Dose Selection for Primary Focal Segmental Glomerular Sclerosis (FSGS)
Session Information
- Pharmacokinetics, Pharmacodynamics, Pharmacogenomics
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics
- 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics
Authors
- Karol, Michael, Retrophin, Inc., Cambridge, Massachusetts, United States
- Pan-Zhou, Xin-Ru, Retrophin, Inc., Cambridge, Massachusetts, United States
- Tuller, Sarah E., Retrophin, Inc., Cambridge, Massachusetts, United States
- Komers, Radko, Retrophin, Inc., Cambridge, Massachusetts, United States
Background
Sparsentan’s dual action is being studied for potential use in the treatment of primary FSGS. This analysis was performed to assess the dose/pharmacokinetic (PK)/pharmacodynamic (PD) relationship of sparsentan in FSGS patients enrolled in the DUET trial, to guide future dose selection.
Methods
The DUET trial determined the sparsentan-induced changes in urine protein/creatinine ratio (Up/C), (baseline to Week 8) in patients assigned to 200 (n=13), 400 (n=21), or 800 (n=30) mg/day. The relationship between sparsentan dose or area under the curve (AUC), and change in Up/C was assessed. PK/PD analyses were based on actual doses received, accounting for dose reductions resulting in PK/PD sample sizes of 17, 23, and 22 for 200, 400, and 800 mg/day, respectively.
Results
Due to small sample sizes, antiproteinuric effects across sparsentan doses were not statistically distinguishable; however, likelihood of a patient having drug exposures resulting in a decrease in Up/C was greater for the 800 mg dose. For the three dose groups, the percentages of patients with a decrease in Up/C were 76%, 74%, and 91%, respectively, as shown in the Figure. Of the 30 patients assigned to the 800 mg dose, 18% experienced hypotension. In general, sparsentan was safe and well tolerated with no clinically significant changes in vital signs or major clinically significant abnormalities in laboratory tests.
Conclusion
Initial daily dosing at 400 mg, followed by escalation to 800 mg for those that tolerate 400 mg, increases the likelihood of antiproteinuric effect while maximizing safety. Both the therapeutic effect vs dose or AUC and AUC distribution analyses each led to the same conclusion.
Funding
- Commercial Support –