J Antimicrob Chemother. 2025 Oct 28:dkaf398. doi: 10.1093/jac/dkaf398. Online ahead of print.
ABSTRACT
OBJECTIVES: This study investigated CYP3A4-mediated pharmacokinetic interactions between ruxolitinib (JAK1/2 inhibitor for steroid-refractory acute and chronic graft-versus-host disease) and posaconazole (antifungal prophylaxis in haematological malignancies) to inform clinical dosing strategies.
METHODS: In this open-label, fixed-sequence trial, eight Chinese patients with haematological malignancies received ruxolitinib 5 mg once daily (Day 1: monotherapy) followed by ruxolitinib 5 mg plus posaconazole 200 mg three times daily (Days 2-6: combination). Plasma concentrations of ruxolitinib and posaconazole were analysed using validated LC-MS/MS. Geometric mean ratios (GMRs) with 90% CIs for PK parameters were calculated to assess PK interactions.
RESULTS: All patients completed the study. Co-administration with posaconazole increased ruxolitinib AUC0-24h by 58% (GMR: 1.58; 90% CI: 1.32-1.88). Geometric mean AUC0-24h values were 179.80 μg·h/L [monotherapy, coefficient of variation (CV) 39.26%] versus 283.60 μg·h/L (combination, CV 41.42%). No significant change in Cmax was observed (GMR: 1.10; 90% CI: 0.90-1.36). Geometric mean of the maximum plasma concentration at steady state (Cmax,ss) and AUC0-24h of posaconazole were 1543.52 μg/L (CV 41.81%) and 31 404.37 μg·h/L (CV 32.14%). There was no significant correlation between the systemic exposure of posaconazole (AUC or Cmax,ss) and the ratio of ruxolitinib AUC0-24h when co-administered versus administered alone.
CONCLUSIONS: Although co-administration of posaconazole with ruxolitinib resulted in a statistically significant increase in ruxolitinib systemic exposure, the magnitude of this interaction was clinically moderate. Although ruxolitinib dose adjustment may not be routinely required when used concomitantly with posaconazole, close monitoring for ruxolitinib-related adverse effects is recommended under this combination therapy setting.
PMID:41148123 | DOI:10.1093/jac/dkaf398
