Background: Ruxolitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of adults with intermediate/high-risk myelofibrosis or polycythemia vera who are resistant or intolerant to hydroxyurea, as well as patients aged ≥12 years with steroid-refractory acute graft-versus-host disease (GVHD) or chronic GVHD after failure of 1–2 lines of systemic therapy. Ruxolitinib tablets are approved in immediate-release (IR) formulations at strengths of 5, 10, 15, 20, and 25 mg taken twice daily (bid). An extended-release (XR) formulation of ruxolitinib is being developed to allow once-daily (qd) treatment administration, which will better accommodate patient preference and potentially enhance patients' long-term treatment compliance. This study assessed ruxolitinib bioequivalence at the study dose of XR 55 mg qd vs IR 25 mg bid under fasted conditions. The findings of this analysis and the dose proportionality of the series of formulations (11, 22, 33, 44, and 55 mg XR) will support license filing of XR qd formulations at doses equivalent to ruxolitinib IR bid.

Methods:This open-label, randomized, 2-period, 2-way crossover study was conducted in healthy adults. Participants were randomized 1:1 into 1 of 2 treatment sequences (IR then XR, or XR then IR). Ruxolitinib IR 25 mg was administered orally bid following a ≥10-hour fast before the morning dose and ≥4-hour fast before the evening dose. Ruxolitinib XR 55 mg was administered orally qd after a ≥10-hour fast. Participants were treated for 4 consecutive days each during 2 treatment periods (Days 1–4 and Days 11–14), separated by a 7-day washout period. Blood samples were collected serially to determine plasma concentrations of ruxolitinib at predefined time points on Days 4 and 14 for a span of 48 hours. Steady-state pharmacokinetic (PK) parameters including minimum observed concentration at steady state (Cmin,ss), observed concentration at 24 hours postdose (C24h,obs,ss),and area under the curve from time 0–24 hours (AUC0–24,ss) were evaluated for bioequivalence. The bioequivalence analysis was performed by analysis of variance using a mixed-effects model with treatment, sequence, and period as fixed effects and participant nested within sequence as a random effect fitted to the natural logarithmic transformed PK parameters. The geometric mean ratio (GMR [ie, point estimate of relative bioavailability]) and 90% CIs for PK parameters between XR and IR formulations were calculated. Relative bioavailability on maximum observed concentration at steady state (Cmax,ss) was also evaluated using the same statistical method.

Results: Samples from 169 participants were included in the analysis; 3 (1.8%) participants discontinued before completing all study treatments and PK sampling by withdrawing consent for personal reasons. Steady state was reached by Day 2 of multiple dosing for both the XR and IR formulations. Ruxolitinib absorption was extended after treatment with the XR formulation, with a median (range) time to Cmax,ss of 3.0 (0.5–11.9) vs 2.0 (0.5–15.0) hours with the IR formulation. As expected, XR displayed a prolonged mean half-lifevs IR (5.4 vs 3.0 hours). The estimated GMRs (90% CI) were within the 0.80–1.25 bioequivalence range for AUC0–24h,ss (1.008 [0.987, 1.029]), Cmin,ss (1.013 [0.920, 1.116]), and C24h,obs,ss (0.923 [0.837, 1.018]). As expected, XR had a lower peak concentration compared with IR, with Cmax,ss approximately 25% lower vs IR overall (GMR: 0.750 [90% CI: 0.721, 0.780]). Fewer participants reported treatment-emergent adverse events after receiving XR vs IR (n=20 [11.8%] vs n=34 [20.2%]); the safety profile of XR was similar to that of IR.

Conclusions:Ruxolitinib XR 55 mg qd demonstrated bioequivalence with ruxolitinib IR 25 mg bid on key measures of drug steady-state exposure (AUC0–24h,ss, Cmin,ss, and C24h,obs,ss), indicating potential for similar clinical benefit. In addition, both the XR and IR ruxolitinib formulations were well tolerated, with similar safety profiles. These findings indicate that qd dosing of the ruxolitinib XR formulation is a suitable alternative to bid dosing of the ruxolitinib IR formulation.

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2025
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