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

Abstract

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 AUC0‐inf of 0.51 (0.49, 0.54) and Cmax of 0.91 (0.84, 0.98). Co‐administration with itraconazole increased the exposures of SHR0302 with GMR (90% CIs) for AUC0‐inf of 1.48 (1.41, 1.56) and Cmax 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.

Computational 3D Modeling-Based Identification of Inhibitors Targeting Cysteine Covalent Bond Catalysts for JAK3 and CYP3A4 Enzymes in the Treatment of Rheumatoid Arthritis

“…The metabolism of JAK inhibitors can also be influenced by other enzymes, including cytochrome P450 3A4 (CYP3A4), which is a cytochrome P450 enzyme found in the liver [ 19 ]. This enzyme plays a crucial role in the metabolism of many drugs, including some JAK inhibitors [ 20 , 21 ]. Inhibition of CYP3A4 can impact the efficacy and safety of treatment by altering the plasma concentrations of drugs metabolized by this enzyme [ 22 ].…”

“…Tofacitinib is a selective inhibitor of JAK3 that is used to treat certain autoimmune diseases, including rheumatoid arthritis, which helps reduce the activity of the immune system [ 15 ]. Tofacitinib is primarily metabolized by the enzyme CYP3A4 [ 23 ], and the inhibition of CYP3A4 can impact the tofacitinib metabolism, potentially leading to drug interactions [ 12 , 20 , 21 ]. Inhibition of CYP3A4 can potentially affect the metabolism and efficacy of tofacitinib, highlighting the importance of considering drug interactions when using it [ 24 , 25 , 26 ].…”