Jérémie Tachet1, Paul Thoueille1,2, Sasisha Nitthaisong2, Francesco Grandoni5, Monika Nagy-Hulliger6, Jörg Halter7, Jakob Passweg7, Nhu-Nam Tran-Thang8, Thierry Buclin1, Laurent A. Decosterd2, François Girardin1,2, Monia Guidi1,3,4
1Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland 2Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland 3Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland 4Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva, Lausanne, Switzerland 5Service and Central Laboratory of Hematology, Lausanne University Hospital, Lausanne, Switzerland 6Service of hematology, Hospital of Morges, Morges, Switzerland 7Service of hematology, Basel University Hospital and University of Basel, Basel, Switzerland 8 Service of medical oncology, Clinique La Source, Lausanne, Switzerland
Objectives: Ruxolitinib is a small molecule targeting JAK1 and JAK2 proteins and used orally for the treatment of myeloproliferative disorders, such as myelofibrosis (MF), Graft-versus-Host disease (GvHD), and polycythemia vera (PV). Dose-response relationship and exposition-dependent tolerability issues have been reported [1, 2]. We hypothesize that efficacy and safety, including adverse events with special interest (AESI), could be improved by determining ruxolitinib plasma concentrations coupled with a population pharmacokinetic (popPK) model for drug exposure optimization. We built a popPK model and analysed patient-related factors influencing ruxolitinib exposition.
Methods: A total of 79 plasma concentrations of ruxolitinib were measured in 26 patients with MF (n = 7), GvHD (n = 16) or PV (n = 3), enrolled in an observational prospective study. Modelling and simulation were conducted with NONMEM®. The popPK model was developed following a stepwise procedure by comparing several compartment models with first-order absorption. Due to limited data to thoroughly characterize the absorption phase, the absorption rate (ka) was fixed at 4 h-1 according to the literature [3] and preliminary model development. The inter-individual variability (IIV) was tested on all PK parameters in a sequential framework, assuming a log-normal distribution. Linear and allometric scaling equations between the parameters and the following covariates, as deemed appropriate, were tested: age, sex, bodyweight, and body mass index (BMI). The effect of sex on ruxolitinib clearance (CL) was investigated generating 1,000 virtual subjects with model-based Monte-Carlo simulations at steady-state for five recommended dosages (5 mg, 10 mg, 15 mg, 20 mg, and 25 mg), allowing comparison of ruxolitinib trough concentrations (Cmin) and PK profiles. Previous published study reported that patients with a Cmin exceeding the threshold of 21.1 ng/mL are at an increased risk of experiencing AESI and other adverse events (AE) of any grade [4]. The percentage of patients above this upper limit was calculated for single dosage.
Results: A one compartment model with first-order absorption and linear elimination best described ruxolitinib data. The residual unexplained variability was accurately characterized by a proportional error model. Parameter estimates of the base model were a CL of 13.2 L/h (IIV: 52.3%) and a central volume of distribution (V) of 62.4 L. The computed Tmax and half-life of elimination were 0.79 h and 3.29 h, respectively. A significant association was found between V and body weight, integrated using allometric scaling with a fixed power of 1, in accordance to previous popPK analyses [3]. Despite the limited number of subjects, covariate analyses revealed an effect of sex on CL: males showed a 34% higher clearance than female, consistent with previously reported values [3, 4].
Model-based simulations suggested that the median Cmin of ruxolitinib were more than two-fold higher in females compared to male. For a dosage of 10 mg twice daily, the Cmin was 11.70 ng/mL [95% predicted interval (PI95): 0.35 – 54.00] for males and 24.30 ng/mL [95% predicted interval (PI95): 2.10– 85.00] for females. Simulations for the same dosage indicated that 26% of males compared to 57% of females were above the toxicity threshold of 21.1 ng/mL. Consistent results were observed across all tested dosages.
Conclusions: Our findings are comparable to those reported in a previously published clinical trials and showed a large inter-individual variability among the population of patients with MF, GvHD, and PV. Simulations revealed an important number of subjects above the previously reported toxicity threshold, with females exhibiting higher trough concentrations across all dosages, potentially increasing their susceptibility to AE, including AESI, compared to males. Given the narrow therapeutic margin and high PK variability, implementing therapeutic drug monitoring for ruxolitinib could address dose-dependent efficacy and safety issues. Further research is needed to determine a disease-specific therapeutic interval to leverage ruxolitinib effectiveness.
References:
[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] Chen X, Williams WV, Sandor V, Yeleswaram S. Population Pharmacokinetic Analysis of Orally-Administered Ruxolitinib (INCB018424 Phosphate) in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET MF). The Journal of Clinical Pharmacology. 2013;53(7):721-30.
[4] 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.
Reference: PAGE 32 (2024) Abstr 10948 [www.page-meeting.org/?abstract=10948]
Poster: Clinical Applications