Evaluation Of Drug-Drug Interactions Of Vx-509 (Decernotinib), An Oral Selective Janus Kinase 3 Inhibitor, In Healthy Human Volunteers

Background Patients with rheumatoid arthritis (RA) often receive multiple medications to manage the signs and symptom of comorbidities. It is therefore important to understand the potential for drug-drug interactions (DDI). VX-509 is an oral selective JAK3 inhibitor being evaluated for the treatment of RA. In vitro studies suggested that VX-509 was a potential inhibitor of transporter P-glycoprotein (P-gp) and that VX-509 had an inactive metabolite that inhibited CYP3A4, a major drug-metabolizing enzyme. Midazolam, a sensitive CYP3A4 substrate, and digoxin, a substrate of P-gp, are commonly used as probes to study DDI potential of CYP3A4 and P-gp inhibitors, respectively. Objectives To assess the drug-drug interactions between VX-509 and midazolam, digoxin, atorvastatin, pravastatin, rosuvastatin, prednisone and methyl-prednisolone. Methods Ninety-eight healthy male and female volunteers were enrolled into 7 groups (N=14 per group). A single oral dose of midazolam (2 mg), digoxin (0.5 mg), atorvastatin (10 mg), rosuvastatin (20 mg), pravastatin (40 mg), prednisone (10 mg), and methyl-prednisolone (8 mg) was given alone and together with VX-509 200 mg once daily (QD) at steady state. Full pharmacokinetic profiles of these drugs were obtained with and without co-administration of VX-509. Geometric least-squares mean (GLSM) ratios (and associated 90% confidence intervals) of AUC and C max of the substrates with/without co-administration of VX-509 were calculated to evaluate the level of interaction. Results VX-509 increased the AUC for midazolam, atorvastatin, and methyl-prednisolone by 12.0-, 2.7-, and 4.3-fold, respectively. VX-509 did not affect the exposure of digoxin, rosuvastatin, pravastatin, and prednisone to a clinically meaningful degree (Table). The drug was generally well tolerated. Conclusions The increase in exposure of midazolam when given with VX-509 suggests that VX-5099s major metabolite is a strong CYP3A4 inhibitor in humans. Dose modifications of certain medicines commonly used in patients with RA (e.g. atorvastatin and methyl-prednisolone) or restrictions of certain medicines (e.g. p.o. midazolam) may therefore be required with VX-509. No dose adjustment would be needed for prednisone, or for pravastatin and rosuvastatin. The absence of an effect on digoxin exposure by VX-509 indicates that no dose adjustments are needed for P-gp substrates. Disclosure of Interest : J. Huang Employee of: Vertex Pharmaceuticals Incorporated, A. Chavan Employee of: Vertex Pharmaceuticals Incorporated, L. Viswanathan Employee of: Vertex Pharmaceuticals Incorporated, X. Luo Employee of: Vertex Pharmaceuticals Incorporated, V. Garg Employee of: Vertex Pharmaceuticals Incorporated, Y. Zhang Employee of: Vertex Pharmaceuticals Incorporated, Y. Xi Employee of: Vertex Pharmaceuticals Incorporated, N. Kinnman Employee of: Vertex Pharmaceuticals Incorporated, L. Mahnke Employee of: Vertex Pharmaceuticals Incorporated DOI 10.1136/annrheumdis-2014-eular.1184