Evaluation of the pharmacokinetic interactions of rezvilutamide (SHR3680) with midazolam, S-warfarin and omeprazole in patients with prostate cancer

Aims: To investigate the potential pharmacokinetic interactions of rezvilutamide on metabolic cytochrome P450 enzymes. Methods: A single-centre open-label, single-arm, fixed-sequence clinical trial was conducted in 18 patients with prostate cancer to evaluate the pharmacokinetic effects of rezvilutamide on the probe drugs for CYP3A4(midazolam), CYP2C9(S-warfarin) and CYP2C19 (omeprazole). Results: After a single oral dose of probe drugs alone and coadministration of rezvilutamide: (1) the geometric mean Cmax of plasma midazolam was 87.129 ng/mL and 7.778 ng/mL, the geometric mean AUC0-t was 273.806 h*ng/mL and 13.630 h*ng/mL, the geometric mean AUC0-∞ was 283.096 h*ng/mL and 14.284 h*ng/mL, the mean t1/2 was 5.347 h and 2.907 h, and the geometric mean CL/F was 52.986 L/h and 1050.102 L/h, respectively; (2) the geometric mean Cmax of plasma S-warfarin was 594.166 ng/mL and 555.228 ng/mL, the geometric mean AUC0-t was 17119.082 h*ng/mL and 9712.186 h*ng/mL, the geometric mean AUC0-∞ was 19510.761 h*ng/mL and 10130.752 h*ng/mL, the mean t1/2 was 38.730 h and 27.794 h, and the geometric mean CL/F was 0.513 L/h and 0.987 L/h, respectively; (3) the geometric mean Cmax of plasma omeprazole was 691.371 ng/mL and 282.064 ng/mL, the geometric mean AUC0-t was 2725.853 h*ng/mL and 599.078 h*ng/mL, the geometric mean AUC0-∞ was 2946.118 h*ng/mL and 661.989 h*ng/mL, the mean t1/2 was 2.612 h and 1.081 h, and the geometric mean CL/F was 6.825 L/h and 30.334 L/h, respectively Conclusion: Coadministration of rezvilutamide with midazolam, S-warfarin and omeprazole may cause loss of activity for these medications. Therefore, appropriate mitigation strategies are recommended.