Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease

Abstract

IntroductionWe report pharmacokinetics of oral ruxolitinib in children with steroid refractory acute graft versus host disease (GVHD) (<12y) and chronic GVHD (≤18y) using our published pediatric dosing. MethodsPK sampling before and +2 hours after ruxolitinib was performed in patients with established chronic GVHD. More extensive PK analysis was evaluated in patients with newly diagnosed acute or chronic GVHD before, +0.5, 1, 2, 4 and 6 hours after ruxolitinib in patients >10kg, and before, +3 and +6 hours in children <10kg. We measured pSTAT1, 3 and 5 expression on CD4+ and CD8+ T-cells before and 2 hours after ruxolitinib as a pharmacodynamic marker of JAK/STAT inhibition. ResultsThirteen patients were prospectively enrolled (0-≤18y with existing chronic GVHD(n=8), 0-<12y with new onset steroid refractory acute GVHD(n=4) and newly diagnosed steroid-refractory chronic GVHD(n=1). A large variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (±SD 4.4; range: 3.1-15.3). The average elimination half-life was 2.32 hours (±SD 1.0). Ruxolitinib clearance was higher in children <2 years versus >2 years (12.1 ± 3.0, vs 5.7 ± 2.8 L/h, p=0.005) and was reduced with concurrent azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T-cells at time of peak ruxolitinib absorption (2 hours after dose). ConclusionsChildren<10 kg have lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variabilities in dosing methods leading to decreased drug absorption.