AB0492 Evaluation of Potential Drug-Drug Interactions with Baricitinib

Background Baricitinib (bari), an oral Janus Kinase (JAK)1/JAK2 inhibitor, is being investigated to treat inflammatory diseases, including rheumatoid arthritis (RA). Baricitinib is primarily cleared renally (75% of the dose is excreted in urine). In vitro studies showed that bari is a substrate for CYP3A4 and the renal transporters, P-glycoprotein (Pgp) and organic anion transporter 3 (OAT3). In vitro studies also showed that bari did not inhibit or induce a panel of CYPs, but did inhibit OAT1, OAT3, organic cation transporter 1 (OCT1), and OCT2. Nevertheless, the potential for clinically meaningful drug-drug interactions (DDIs) is predicted to be low, as the unbound Cmax/IC50 ratios were all Objectives Confirm lack of clinically relevant DDIs in clinical pharmacology (CP) studies. Methods Seven CP studies in healthy subjects (HS) and 1 CP study in patients with RA were conducted. Studies in HS examined the potential for bari to be a CYP3A, CYP2C19, or CYP2C9 substrate, a Pgp or OAT3 substrate, a Pgp inhibitor, or a CYP3A inducer or inhibitor. Methotrexate (MTX), a substrate of several transporters and a commonly used medication for RA, was studied in combination with bari in patients with RA. Each study was powered to evaluate statistically significant differences in exposure. Results In HS, co-administration of the CYP3A inhibitor (ketoconazole) or the CYP2C19/CYP2C9/CYP3A inhibitor (fluconazole) with bari had no significant effects on the pharmacokinetics (PK; AUC and C max ) of bari. Rifampicin, a potent CYP3A inducer, decreased bari AUC by 34% without affecting C max . The Pgp inhibitor, ciclosporin, increased bari AUC by 29% and t max , by 1 hour without affecting C max . Probenecid, a potent OAT3 inhibitor, had no effect on bari C max , but decreased renal clearance by 69% and increased AUC by 2-fold. When tested as a possible Pgp inhibitor or as a possible CYP3A inducer, bari had no effect on the PK of digoxin or the components of Microgynon® (Bayer, United Kingdom), respectively. When tested as a possible CYP3A inhibitor, bari decreased the exposure of simvastatin (AUC: -15%; C max : -29%) and its active metabolite (AUC: -16%; C max : -12%), consistent with a modest decrease in absorption, without CYP3A interaction. The combination of MTX and bari in patients with RA had no significant effect on the PK of bari or MTX. Baricitinib was well tolerated in all CP DDI studies. Conclusions Potential interactions between bari and various drug transporter and CYP substrates, inhibitors, and inducers were evaluated. In most studies, including those evaluating CYP effects, no clinically significant interactions were seen. Probenecid, a strong inhibitor of the transporter OAT3, reduced bari clearance. The current data indicate a low risk of clinically significant DDIs between bari and other drugs that may be concomitantly administered to patients with RA. Disclosure of Interest C. Payne Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co., X. Zhang Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co., N. Shahri Employee of: inVentiv Health Clinical, W. Williams Shareholder of: Incyte Corp., Employee of: Incyte Corp., E. Cannady Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co.