Pharmacokinetics and Pharmacodynamics of RPC1063 and Its Metabolites in Healthy Adult Volunteers (P1.211)

OBJECTIVE: Evaluate the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of RPC1063 and its metabolites. BACKGROUND: RPC1063 is a potent, selective and orally available small molecule sphingosine 1-phosphate-1 receptor (S1P1R) agonist in development for treating relapsing multiple sclerosis (RMS). DESIGN/METHODS: The PK of RPC1063 and its metabolites in plasma were evaluated in two Phase I studies using a validated LC-MS/MS method and a non-compartmental method. Lymphocyte reduction was monitored as a pharmacodynamic biomarker. Metabolites were characterized in a series of in vitro and in vivo studies to evaluate their safety, pharmacology and drug-drug interaction potential. RESULTS: As observed in preclinical toxicology species (rat and monkey), RPC1063 was biotransformed in humans to metabolites RP101988 and RP101075; both metabolites share the potency and selectivity of RPC1063 towards S1P1R. At steady state, RPC1063, RP101988 and RP101075 comprised 39%, 49%, and 11% of the total plasma AUC, respectively. The PK of the metabolites was similar to that of RPC1063, characterized by a late T max (6-8 hrs), an elimination half-life of 19-22 hours and low inter-subject variability. Across subjects, ratios of metabolite to parent exposures were similar and the PK of total agonist (sum of RPC1063 and metabolite concentrations) showed low variability (%CVs 20% and 19% for C max and AUC). The extent of lymphocyte reduction at steady state correlated well with both parent and total agonist exposures. Like RPC1063, the metabolites are not inhibitors of CYP450 enzymes or the hERG channel, have similar binding to human plasma proteins, and have been qualified in chronic GLP toxicology studies. Biotransformation of RPC1063 is mediated by both CYP450 enzymes and dehydrogenases; redundancies in the enzymatic pathways are anticipated to minimize the potential of drug-drug interactions with RPC1063 or metabolites as victims. CONCLUSIONS: RPC1063 and its two pharmacologically active metabolites have a favorable PK profile for the treatment of RMS. Study Supported by: Receptos, Inc. Disclosure: Dr. Timony has received personal compensation for activities with Receptos Inc. as an employee. Dr. Timony holds stock and/or stock options in Receptos Inc. which sponsored research in which Dr. Timony was involved as an investigator. Ms. Brooks has received personal compensation for activities with Receptos Inc. as an employee. Ms. Brooks holds stock and/or stock options in Receptos Inc. Dr. Hartung has received personal compensation for activities with Receptos Inc., as an employee. Dr. Scott has received personal compensation for activities with Receptos Inc. Dr. Scott holds stock and/or stock options in Receptos Inc. Dr. Olson has nothing to disclose. Dr. Gujrathi has received personal compensation for activities with Receptos as an employee. Dr. Gujrathi holds stock and/or stock options in Receptos. Dr. Boehm has received personal compensation for activities with Receptos Inc. as an employee. Dr. Boehm holds stock and/or stock options in Receptos Inc. Dr. Peach has received personal compensation for activities with Receptos Inc. as an employee. Dr. Peach holds stock and/or stock options from Receptos Inc.