SP124IN VITRO EVALUATION OF INDUCTION OF CYTOCHROME P450 ENZYMES BY SPARSENTAN AND EFFECTS OF ITS METABOLISM BY POTENTIAL
Xin-Ru Pan-Zhou, Kevin Leach · Nephrology Dialysis Transplantation · 2017
INTRODUCTION AND AIMS: Sparsentan is a first-in-class, potent, dual endothelin type A (ETA) and angiotensin type 1 (AT-1) receptor antagonist currently in clinical development for potential treatment of primary focal segmental glomerular sclerosis (FSGS). Here we report the effects of sparsentan on the mRNA expression and enzyme activities of the cytochrome P450 (CYP) enzymes and in vitro evaluation the potential for drug-drug interactions (DDI) with drugs that may be co‑administered with sparsentan. METHODS: Cryopreserved human hepatocytes from three donors in primary cultures were treated with sparsentan up to 250 µM for 72 hours. Catalytic activity and mRNA expression were then measured for CYP1A2, CYP2B6, and CYP3A4/5. The potential DDIs due to CYP inhibition were assessed by incubating sparsentan with likely co‑administered drugs in human liver microsomes (HLM). The potential DDIs due to CYP induction were determined by the rates of sparsentan metabolism by hepatocytes treated for 72 hours with vehicle and potential co‑administered drugs. The concentration of sparsentan was 5 µM whereas the concentrations of likely co‑administered drugs were 1- and 10-fold their reported efficacious plasma Cmax levels. RESULTS: Sparsentan had little or no effect on the induction of CYP1A2. However increased expression of mRNA and enzyme activies were detected for CYP2B6 and CYP3A4/5. After treating hepatocytes with rifampicin (20 µM) as a positive control for CYP3A4/5 induction, the remaining mean sparsentan concentrations was 82.5% (66.0% to 95.7%) of vehicle control. Hepatoctyes treated with torsemide at 10-fold Cmax, led to remaining mean sparsentan concentrations of 83.7% (74.8% to 89.1%). Incubation with either atorvastatin, cerivastatin, pravastatin, prednisone or simvastatin up to 10-fold their respective Cmax concentrations, resulted in sparsentan concentrations that were ≥86.2% of the vehicle control. Sparsentan was metabolized by pooled Human liver microsomes (HLM) in the presence of NADPH. Cyclosporine A and voriconazole, CYP3A inhibitiors, but not fluvastatin and fenofibrate (2C8 and 2C9 inhibitors), showed concentration-dependent inhibition of sparsentan metabolism of 17.5% and 32.7% at their plasma Cmax, respectively, and 69.6% and 64.8% at their plasma 10-fold Cmax, respectively. CONCLUSIONS:In vitro CYP induction assessment indicated that sparsentan is an inducer for CYP2B6 and CYP3A4/5, but not CYP1A2. While sparsentan is primarily metabolized by CYP3A4 and is also a CYP3A4 weak inhibitor, in vitro studies indicated the metabolism of sparsentan could be enhanced in hepatocytes by some of the drugs (rifampicin and torsemide) or inhibited in HLMs by some of CYP3A inhibitors (cylosporine A and voriconazole). Clinical studies are underway using some of the same probes used in the in vitro studies to define the potential for DDIs with co-administered medications that are metabolized by CYP3A and/or CYP2B6.