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 Cmax 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-509's 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