Drug–Drug Interaction Assessment of WXFL10203614 with Rifampicin, Itraconazole and Metformin: A Three-Cohort Phase I Study
Abstract
Abstract Aims 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. Methods In this single-centre, open-label, fixed-sequence, self-controlled Phase I study, 54 healthy participants were enrolled into 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 prespecified PK parameters. Results 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), suggesting that the interactions primarily affected drug disposition after absorption. At steady state, WXFL10203614 produced no clinically meaningful change in metformin plasma exposure; however, metformin renal clearance and cumulative urinary excretion decreased by approximately 36% and 30%, respectively. These changes were consistent with an effect on renal tubular secretion involving MATE1/MATE2-K. No serious adverse events occurred, and most treatment-emergent adverse events were Grade 1. Conclusions WXFL10203614 was sensitive to…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 54 participants or records.
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