Ruxolitinib Pharmacokinetics and Exposure-Toxicity Relationship in Hematologic Malignancies and Immune-Mediated Diseases: A Prospective Observational Study.

Ruxolitinib pharmacokinetics (PK) has been characterized in clinical trials but remains poorly documented in real-world practice. This project aimed to investigate ruxolitinib PK in routine clinical practice, identify factors driving its variability, and explore exposure-response relationships to assess the potential role of therapeutic drug monitoring. In total, 221 steady-state ruxolitinib concentrations from 77 adult patients enrolled across several centers in Switzerland were analyzed. Demographic and clinical data were recorded at each visit. Population pharmacokinetic (popPK) analysis was performed with MonolixSuite® 2024R1 (Lixoft, France). Model-based simulations were used to predict trough concentration (Cmin) and the area under the concentration-time curve over 24 h (AUC24) for the recommended dosage regimens, as a function of covariates. An exploratory pharmacokinetic/pharmacodynamic analysis was conducted in the overall cohort. Ruxolitinib PK was characterized by a marked between-subject variability in clearance (45%). Strong cytochrome (CYP) 3A4 or dual CYP2C9/CYP3A4 inhibitors reduced clearance by 39%. At 10 mg twice daily, model-based simulations showed CYP inhibitors increased median Cmin and AUC24 by 2.9- and 1.7-fold, respectively. Still, no significant exposure-efficacy relationship was identified. However, higher ruxolitinib exposure tended to be associated with increased toxicity in the overall population (Cmin and AUC24, P≈0.02-0.03). In clinical practice, ruxolitinib exposure shows substantial variability and is strongly affected by strong CYP inhibitors that are frequently co-administered. Whilst no clear exposure-efficacy relationship was observed, higher exposure was linked to increased toxicity risk, arguing for careful dose adjustment.