Review Finds Good Understanding of Pharmacokinetics of Ruxolitinib, but Questions Remain

The pharmacokinetics and pharmacodynamics of ruxolitinib (Jakafi) are well understood, but more research is needed to better understand why some patients respond differently than others, according to a new report published in Clinical Pharmacokinetics.

The review also offers insights into how the medication affects people with liver and renal dysfunction.

Ruxolitinib is a tyrosine kinase inhibitor (TKI) that is used to treat patients with myelofibrosis, polycythemia vera, and steroid-refractory graft-versus-host disease undergoing allogeneic stem cell transplantation, noted the study authors. It works by targeting the Janus kinase and signal transducer and activator of transcription pathways, they added.

After examining the existing literature, the investigators said ruxolitinib is well absorbed and has bioavailability of more than 95% and protein binding to albumin of approximately 97%. They said its pharmacokinetics can be described with a 2-compartment model and linear elimination.

The authors said the volume of distribution of the drug varies between men and women. They said males have a higher clearance than women: 22.1 vs 17.7 L/h.

“This could be explained by the differences in bodyweight,” the authors noted. “However, both males and females showed a lack of relationship between clearance and weight.”

Metabolism of ruxolitinib is mainly hepatic via the cytochrome P450 (CYP) enzyme CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. They said it is not known whether CYP3A5 plays a role in ruxolitinib metabolism, but CYP2C9 appears to play a minor role.

They said the main route of elimination of the drug’s metabolites is renal. “Therefore, renal dysfunction can increase the exposure of active metabolites of ruxolitinib,” they added.

The authors said one earlier study looked at the impact of a 25-mg dose of ruxolitinib in patients with all stages of renal impairment. The major finding was that the pharmacokinetic variables of ruxolitinib were not affected by renal dysfunction, while T_½ [half-life] and AUC_0-∞ [area under the plasma concentration–time curve from zero to infinity] of the metabolites increased with severity of renal impairment,” they said.

Turning to patients with liver dysfunction, the investigators noted a study of patients with various stages of hepatic impairment who were given the same 25-mg dose. That study found that the peak serum concentration of the drug was unchanged in all patient groups, but they said the AUC_0-∞ in the mild, moderate, and severe impairment groups was significantly higher than in healthy controls.

The authors said some patients with liver and renal dysfunction might require dose reductions. Model-informed precision dosing (MIPD) might be a useful tool to optimize individual dosing to better balance efficacy and adverse events, the investigatore said, adding that such dosing might help account for drug-drug interactions.

“Most TKIs are substrates for CYP3A4 enzymes and are susceptible to enzyme inhibition and enzyme induction increasing pharmacokinetic variability and exposure,” they wrote.

The authors said MIPD is typically not used for ruxolitinib, but they said it might make sense for some cases.

“Taken together, the evidence is currently too limited to support ruxolitinib MIPD in routine clinical practice,” they said. “However, for complex individual cases, MIPD might be of value.”

Reference

Appeldoorn TYJ, Munnink THO, Morsink LM, Hooge MNL, Touw DJ. Pharmacokinetics and pharmacodynamics of ruxolitinib: a review. Clin Pharmacokinet. 2023;62(4):559-5711-13. doi:10.1007/s40262-023-01225-7