Sustained‐release ruxolitinib: Findings from a phase 1 study in healthy subjects and a phase 2 study in patients with myelofibrosis

Abstract

Ruxolitinib is the first Janus kinase (JAK) inhibitor approved for the treatment of myelofibrosis, where its efficacy is often associated with cytopenia. It is possible that the severity of cytopenia is in part driven by C max. A once‐daily sustained‐release (SR) formulation of ruxolitinib was therefore developed to decrease the C max/C min ratio relative to twice‐daily immediate‐release (IR) ruxolitinib. An SR formulation was identified based on pharmacokinetic evaluation in a phase 1 study in healthy adults (N = 9). This was followed by an open‐label phase 2 study in patients with myelofibrosis (N = 41). Ruxolitinib SR treatment was well tolerated with blood cell counts relatively unchanged through week 16. In terms of efficacy, 7 patients (17.1%) had clinical improvement and 33 (80.5%) had stable disease. While this study has raised the possibility of an increased therapeutic index for ruxolitinib via an SR formulation, further studies are required to validate the hypothesis.

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review

“…In order to decrease C max , and to reduce the risks of adverse events, a study with modified-release preparations was performed [ 38 ]. Two different sustained-release (SR) formulations of ruxolitinib, SR-1 and SR-2, were compared with the commercially available IR formulation.…”

“…An interesting finding was that both clearance for SR (18.3 vs 34.8 L/h) and volume of distribution ( V c /F) during the terminal phase (218 vs 304 L) were lower in women than in men. For IR ruxolitinib, a sex-based difference in clearance was also found [ 38 ]. Two other studies found the same results for sex-based difference for volume of distribution [ 34 , 38 ].…”

“…For IR ruxolitinib, a sex-based difference in clearance was also found [ 38 ]. Two other studies found the same results for sex-based difference for volume of distribution [ 34 , 38 ].…”

“…The mean C max and AUC 0-∞ increased in a linear manner indicating a non-saturable clearance [ 32 , 36 ]. The previously discussed study with two different SR formulations and an IR formulation found that the T ½ of SR-1 and SR-2 formulations was almost two times longer compared with the IR formulation, 5.3 and 6.1 h versus 2.8 h. The CL/F was almost the same for IR, SR-1 and SR-2, respectively 22.8 L/h, 27.2 L/h and 24.6 L/h [ 38 ]. These differences can be explained by the different characteristics of IR and SR formulations.…”

Carfilzomib Enhances the Suppressive Effect of Ruxolitinib in Myelofibrosis

“…Next, the proteasome machinery was investigated as a target in CD34 + cells from MF patients. We used 300 nM ruxolitinib which is a value between the ruxolitinib C max of 1100 nM after a single oral dose of 25 mg and the concentration of 45.6 nM after 12 h (when the next dose is given) [ 28 ]. The in vitro treatment of CD34 + cells from three patients (MF#3, #10, #15) showed that CFZ at 10 or 50 nM had a significant inhibitory effect on MF cells at 24 h and the inhibition further increased at 72 h, as shown for MF#3 ( Figure 3 C).…”