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SAT0227 The Effect of Deuteration of VX-509 (Decernotinib) on Drug-Drug Interactions (DDI) with Midazolam
  1. J. Huang,
  2. F. Yang,
  3. J. Yogaratnam,
  4. J. Shen
  1. Vertex Pharmaceuticals Incorporated, Boston, United States

Abstract

Background VX-509 is an oral selective Janus Kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis (RA). In vitro and in vivo studies suggest that a major metabolite of VX-509, VRT-1123001 (M3) is a potent inhibitor of Cytochrome P450 3A4 (CYP3A4). It was hypothesized that deuteration of VX-509 could decrease the formation of M3 in vivo and consequently reduce the inhibition of CYP3A4. Midazolam (MDZ), a sensitive CYP3A4 substrate, is commonly used as a probe to study the potential DDI of CYP3A4 inhibitors.

Objectives To evaluate the effect of deuteration on the extent of DDI between VX-509 and MDZ in healthy subjects.

Methods Fourteen healthy subjects (ages 23-52 years, 12 female and 2 male) were randomized into two cohorts and received 4 treatments in a partial crossover design - (A) single oral dose of MDZ 2 mg; (B) [2H]-VX-509 100 mg once daily (qd) on Days 1-8; (C) VX-509 100 mg qd on Days 1-8; (D) [2H]-VX-509 200 mg qd on Days 1-8. Treatments B, C and D all received an oral dose of MDZ 2 mg on Day 7. Full PK profiles of MDZ and its metabolite, [2H]-VX-509, VX-509 and M3 were obtained. Geometric least-squares mean (GLSM) ratios (and associated 90% confidence intervals) of AUC0–∞) and Cmax of MDZ with and without coadministration of [2H]-VX-509 or VX-509 were calculated to evaluate the extent of DDI.

Results [2H]-VX-509 100 mg qd increased MDZ exposure by 4.2-fold, significantly less than that of VX-509 100 mg (6.9-fold, p<0.05), indicating that [2H]-VX-509 is a moderate CYP3A4 inhibitor at 100 mg qd and that deuteration reduced the extent of DDI with CYP3A4 substrates [Table 1]. Deuteration of VX-509 reduced the systemic exposure to M3 without affecting the exposure to VX-509 following doses of 100 mg qd [Table 2]. The effect of [2H]-VX-509 on MDZ exposure was approximately 2-fold higher following 200 mg qd dose than that following 100 mg qd dose. The most common treatment emergent AE was nervous system disorders (N=2). Both VX-509 and [2H]-VX-509 were generally safe and well tolerated.

Conclusions Deuteration of VX-509 significantly reduced the extent of DDI between VX-509 and MDZ without affecting the exposure to VX-509 in healthy subjects. These results suggest deuteration could be a useful method to improve the clinical DDI profile of a compound.

Disclosure of Interest J. Huang Shareholder of: Vertex, Employee of: Vertex, F. Yang Shareholder of: Vertex, Employee of: Vertex, J. Yogaratnam Shareholder of: Vertex, Employee of: Vertex, J. Shen Shareholder of: Vertex, Employee of: Vertex

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