Effect of CYP3A4 induction and inhibition on the pharmacokinetics of SHR0302 in healthy subjects

Aims: SHR0302 is a selective Janus kinase (JAK) 1 inhibitor under clinical investigation for the treatment of rheumatoid arthritis (RA). As SHR0302 is metabolized mainly by cytochrome P450 (CYP) 3A4, clinical studies were performed to evaluate the effects of a strong CYP3A4 inducer, rifampin, and a strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of SHR0302 in healthy subjects.

Methods: Two phase I, open-label, fixed-sequence drug interaction studies enrolled 28 subjects. In Study A, 14 subjects received 8 mg SHR0302 on Days 1 and 10, and 600 mg rifampin once daily on Days 3-11. In Study B, 14 subjects received 4 mg SHR0302 on Days 1 and 8, and 200 mg itraconazole once daily on Days 4-10. Blood samples were collected to measure SHR0302 concentrations. Pharmacokinetic parameters were calculated using non-compartmental analysis. Treatment comparisons were made using mixed-effect models.

Results: Co-administration with rifampin decreased the exposures of SHR0302 with geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC_0-inf of 0.51 (0.49, 0.54) and C_max of 0.91 (0.84, 0.98). Co-administration with itraconazole increased the exposures of SHR0302 with GMR (90% CIs) for AUC_0-inf of 1.48 (1.41, 1.56) and C_max of 1.06 (0.982, 1.14). Single oral doses of SHR0302 administered with or without rifampin or itraconazole were generally safe.

Conclusions: Strong CYP3A4 induction and inhibition both resulted in a weak effect on the clinical exposures of SHR0302. These present studies provided valuable information that helps inform SHR0302 dosing instructions and concomitant medication precautions.