Author Of 1 Presentation
P0343 - Inhibition of drug transporter breast cancer resistance protein has no effect on the pharmacokinetics of major active metabolites of ozanimod (ID 1170)
Abstract
Background
Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis. A previous study showed that co-administration of ozanimod with cyclosporine had no effect on ozanimod exposure but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273). CC112273 and its interconverting active metabolite CC1084037 were not monitored in that study. A new study (NCT04149678) was conducted to further investigate this potential drug-drug interaction, particularly on the major active metabolites.
Objectives
This study’s primary objective was to evaluate the effect of cyclosporine, the index inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics (PK) of ozanimod, CC112273, CC1084037, and RP101988.
Methods
In this phase 1, randomized, parallel-group, open-label study (NCT04149678), 40 healthy adult subjects were enrolled and randomly assigned to 1 of 2 treatment groups (20 per group). Group A received a single oral dose of ozanimod 0.46 mg, and group B received a single oral dose of ozanimod 0.46 mg plus a single oral dose of cyclosporine 600 mg. PK blood samples were collected up to 336 hours postdose, and PK parameters for ozanimod, CC112273, CC1084037, and RP101988 were calculated. Point estimates and 90% confidence intervals (CIs) for the geometric mean ratio between treatment groups (B vs A) for maximum concentration (Cmax) and overall exposure (AUC0-last) were determined with an analysis of variance.
Results
Cyclosporine increased exposure of the minor active metabolite RP101988 approximately 2-fold. Point estimates and 90% CIs for RP101988 Cmax and AUC0-last were 1.96 (1.70, 2.25) and 1.75 (1.47, 2.09), respectively. However, cyclosporine had no effect on ozanimod and its major active metabolites. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 Cmax were 1.01 (0.88, 1.15), 0.87 (0.75, 1.003), and 0.99 (0.87, 1.14), respectively. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 AUC0-last were 1.07 (0.92, 1.26), 1.02 (0.85, 1.22), and 1.11 (0.71, 1.72), respectively.
Conclusions
Results from this new study indicate that coadministration of ozanimod with inhibitors of BCRP had no effect on the exposure of ozanimod and its major active metabolites.