Jérémie Tachet1, Paul Thoueille1, Francesco Grandoni2, Monika Nagy-Hulliger3, Jörg Halter4, Prof. Jakob Passweg4, Nhu-Nam Tran-Thang5, Carine Bardinet1, Laurent A. Decosterd1, François R. Girardin1, Monia Guidi1,6,7
1Service and Laboratory of Clinical Pharmacology, University Hospital and University of Lausanne, 2Service and Central Laboratory of Hematology, University Hospital of Lausanne, 3Service of Hematology, Hospital of Morges, 4Service of Hematology, University Hospital and University of Basel, 5Service of Medical Oncology, Clinique La Source, 6Center for Research and Innovation in Clinical Pharmaceutical Sciences, Department of Education and Research, University Hospital and University of Lausanne, 7Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne
Objectives Ruxolitinib is an orally administered small-molecule that inhibits the isomers JAK1 and JAK2 for treatment of myelofibrosis (MF), Graft-versus-Host Disease (GvHD), and polycythaemia vera (PV). Previous studies highlighted dose-response relationships and exposure-dependent safety concerns [1-3]. Ruxolitinib is primarily metabolized by CYP3A4, making it particularly susceptible to drug-drug interactions. This study aimed to characterize ruxolitinib pharmacokinetics (PK) and to assess covariates influencing its exposure in a real-world setting. Methods Population modeling and simulations (NONMEM®) were performed using data from a prospective observational study, which enrolled adults (= 18 years old) taking ruxolitinib. A classical stepwise strategy comparing several compartmental models with linear absorption and elimination was employed. The inter-individual variability (IIV) was assessed for all PK parameters. The tested covariates were evaluated for significance using linear and allometric scaling equations and included demographic factors [age, sex, body weight (BW), and body mass index], creatinine, and other clinical factors (strong CYP3A4 inhibitors, disease). BW was tested a priori on clearance (CL) and the volume of distribution (V) with allometric scaling of power 0.75 and 1, respectively. Model-based simulations were conducted generating 1,000 virtual subjects for the recommended dosage of 10 mg to investigate the effect of influential covariates by comparison of the ruxolitinib minimal concentration (Cmin). An exploratory pharmacokinetic/pharmacodynamic (PK/PD) analysis using logistic regression was performed to assess the concentration-toxicity relationship. This analysis assessed the risk of adverse events (AEs) occurrence, regardless of grade or type, in relation to the individual predicted Cmin. Results A total of 160 ruxolitinib plasma concentrations from 50 patients diagnosed with MF (n = 13), GvHD (n = 28), PV (n = 4), and other off-label indications (n = 5) were available for the analysis. The PK of ruxolitinib was best captured by a one-compartment model with first-order absorption and linear elimination. Residual unexplained variability was described using a proportional error model. The estimated parameters for the base model included an absorption rate constant (ka) of 4.25 h?¹, a CL of 14.5 L/h [IIV (%CV): 48%], and a V of 78 L. The calculated Tmax and t1/2 were 0.77 h and 3.72 h, respectively, and were in line with the literature. Covariate analysis revealed that strong CYP3A4 inhibitors significantly reduced CL by 42%, compared to patients on moderate and no inhibitors, consistent with previous findings [3, 4]. Model-based simulations demonstrated that the median Cmin of ruxolitinib was more than three times higher in patients receiving strong CYP3A4 inhibitors [Cmin, 10mg: 12.0 ng/mL, 95% prediction interval (PI95): 0.4–52.0 ng/mL] than in those without [Cmin, 10mg: 38.0 ng/mL, PI95: 5.0–124.0 ng/mL]. The exploratory PK/PD analysis could not reveal a significant association between Cmin and the probability of experiencing at least one AE (P > 0.05). Still, previous studies [3, 5] demonstrated an exposure–toxicity relationship, suggesting that AEs might be underreported. Based on a previous study [4] and on the significant reduction in CL observed with strong CYP3A4 inhibitors, a dose reduction could be considered in patients with GvHD, where posaconazole is frequently co-prescribed. Phenoconversion with reduced CYP3A4 function associated with high disease-driven inflammatory activity might be a further causal factor. Conclusions Our findings are consistent with previous clinical studies showing significant variability in ruxolitinib exposure. CYP3A4 inhibitors significantly increased ruxolitinib Cmin, while exploratory PK/PD analysis suggested that higher Cmin were not associated with toxicity in our population. Further research is needed to define disease-specific therapeutic ranges for ruxolitinib doses optimization.
[1] Le RQ, Wang X, Zhang H, Li H, Przepiorka D, Vallejo J, et al. FDA Approval Summary: Ruxolitinib for Treatment of Chronic Graft-Versus-Host Disease after Failure of One or Two Lines of Systemic Therapy. The Oncologist. 2022;27(6):493-500. [2] Plosker GL. Ruxolitinib: A Review of Its Use in Patients with Myelofibrosis. Drugs. 2015;75(3):297-308. [3] Isberner N, Kraus S, Grigoleit GU, Aghai F, Kurlbaum M, Zimmermann S, et al. Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice—a prospective single-center trial. Cancer Chemother Pharmacol. 2021;88(6):973-83. [4] Shi JG, Chen X, Emm T, Scherle PA, McGee RF, Lo Y, et al. The Effect of CYP3A4 Inhibition or Induction on the Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phosphate) in Healthy Volunteers. The Journal of Clinical Pharmacology. 2012;52(6):809-18. [5] Incyte Corp. Jakafi. Clinical Pharmacology and Biopharmaceutics review(s). U.S. Food and Drug Administration (FDA) website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/202192Orig1s000.pdf Accessed [01.2025].
Reference: PAGE 33 (2025) Abstr 11691 [www.page-meeting.org/?abstract=11691]
Poster: Drug/Disease Modelling - Other Topics