Fevipiprant has a low risk of influencing co-medication pharmacokinetics: Impact on simvastatin and rosuvastatin in different SLCO1B1 genotypes

Fevipiprant, a prostaglandin D receptor 2 antagonist, is in clinical development as a treatment for asthma. The goal of this study was to assess the potential of fevipiprant to cause drug-drug interactions (DDI) as a perpetrator, that is, by altering the pharmacokinetics (PK) of co-medications. In vitro drug interaction studies of clinically relevant drug metabolizing enzymes and transporters were conducted for fevipiprant and its acyl glucuronide (AG) metabolite. Comparison of K values with unbound systemic or portal vein steady-state plasma exposure of fevipiprant and its AG metabolite revealed the potential for inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) transporters (R-value of 5.99), while other targets including cytochrome P450 enzymes were not, or only marginally, inhibited. Consequently, an open-label, two-part, two-period, single-sequence clinical study assessed the effect of fevipiprant 450 mg QD on the pharmacokinetics of simvastatin 20 mg and rosuvastatin 20 mg, two statins with different dependency in OATP1B1-mediated hepatic uptake, in healthy adult volunteers. The study also assessed the pharmacogenetics of the SLCO1B1 gene, which encodes OATP1B1. Clinically, fevipiprant 450 mg QD showed a low potential for interaction and increased the peak concentrations of simvastatin acid and rosuvastatin by 2.23- and 1.87-fold, respectively, with little or no impact on total exposure. Genotype analysis confirmed that SLCO1B1 genotype influences statin pharmacokinetics to a similar extent either with or without fevipiprant co-administration. In summary, fevipiprant at 450 mg QD has only minor liabilities as a perpetrator for DDI.