Abstract
PurposeKnowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects.Methods262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed.ResultsMedian of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6–99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05).ConclusionRuxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.
Highlights
Graft versus host disease (GvHD) remains to be one of the major causes for morbidity and mortality after allogeneic hematopoietic stem cell transplantation with 30–60% of recipients developing acute GvHD and 30–70% developing chronic GvHD [1,2,3,4]
In May 2019, Ruxolitinib was approved by the US Food and Drug administration (FDA) for treatment of SR-acute GvHD (aGvHD) based on the REACH1 trial [12]
They reported a median Css min of 11 ng/mL, a pharmacokinetic study conducted in eight healthy individuals found a Css min of approximately 20 ng/mL at 30 mg daily [27] and the analysis of one Css min in a MF patient showed a concentration of 15.8 ng/mL at 5 mg daily [32]
Summary
Graft versus host disease (GvHD) remains to be one of the major causes for morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with 30–60% of recipients developing acute GvHD (aGvHD) and 30–70% developing chronic GvHD (cGvHD) [1,2,3,4]. Treatment with corticosteroids comes along with severe toxicities while 40% of patients with aGvHD and 50–60% of patients with cGvHD do not show sustained responses [5,6,7,8]. Treatment for both acute and chronic steroid-refractory GvHD (SR-GvHD) comprise variable immunosuppressants, most of which are not approved for GvHD. Ruxolitinib is not yet approved for treatment of SR-cGvHD, but primary findings of the REACH3 trial are promising with significantly greater overall response rate and improvements in failure-free survival and patient-reported symptoms in patients receiving Ruxolitinib compared to best available therapy [14]
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