Abstract
<jats:p><b>Aims:</b> To evaluate the effects of rifampicin and itraconazole on the pharmacokinetics (PK) of the Janus kinase 1 (JAK1) inhibitor WXFL10203614 and the effects of steady-state WXFL10203614 on the PK and safety of metformin. <b>Methods:</b> In this single-centre, open-label, fixed-sequence, self-controlled Phase I study, 54 healthy participants were assigned to three cohorts. Plasma and urine drug concentrations were determined using validated liquid chromatography–tandem mass spectrometry. Drug–drug interactions were assessed using geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for key PK parameters. <b>Results:</b> Rifampicin reduced WXFL10203614 systemic exposure by approximately 40% and shortened its elimination half-life by 39%, whereas itraconazole increased exposure by approximately 26% compared with WXFL10203614 alone. Neither treatment produced a clinically meaningful change in maximum plasma concentration (Cmax), indicating that the interactions mainly affected drug elimination. Steady-state WXFL10203614 did not significantly alter metformin plasma exposure but reduced renal clearance and cumulative urinary excretion by approximately 36% and 30%, respectively, consistent with inhibition of multidrug and toxin extrusion (MATE)-mediated renal secretion. No serious adverse events occurred, and most treatment-emergent adverse events were Grade 1. <b>Conclusions:</b> Rifampicin markedly reduced WXFL10203614 exposure and should be avoided during concomitant administration, whereas dose adjustment is unlikely to be required with itraconazole. WXFL10203614 may inhibit the renal elimination of metformin through MATE-mediated mechanisms; therefore, caution is warranted when it is co-administered with metformin or other MATE substrates. These findings support clinical dosing recommendations for WXFL10203614.</jats:p>