Deuruxolitinib

Deuruxolitinib is a Janus kinase (JAK) inhibitor. JAKs mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

In an in vitro kinase activity assay, deuruxolitinib had greater inhibitory potency for JAK1, JAK2 and TYK2 relative to JAK3. The relevance of inhibition of JAK enzymes to therapeutic effectiveness is not currently known.

Deuruxolitinib Inhibition of IL-6 Induced STAT3 Phosphorylation

Deuruxolitinib inhibited whole blood IL-6 stimulated pSTAT3 in healthy subjects 2 hours post-dose. The relevance of this finding in patients is unknown.

Cardiac Electrophysiology

At concentrations approximately 4-fold higher than the C_max associated with the highest dose evaluated clinically, 12 mg twice-daily, deuruxolitinib does not prolong the QT interval to any clinically relevant extent.

Following oral administration of deuruxolitinib, C_max and AUCs increased dose proportionally over a dose range from 8 mg to 48 mg (6 times the approved recommended dosage) in healthy subjects. Steady-state plasma concentrations were achieved within 1 to 2 days, with minimal accumulation, after twice daily administration.

Absorption

Deuruxolitinib bioavailability is 90%, with peak plasma concentrations reached within 1.5 hrs.

Effect of Food

No clinically significant differences in the pharmacokinetics of deuruxolitinib were observed following administration of a high fat, high calorie meal (approximately 50% fat and 800-1000 calories).

Distribution

The deuruxolitinib steady state volume of distribution is approximately 50L. Deuruxolitinib plasma protein binding is 91.5% and blood to plasma concentration ratio is approximately 1.3.

Elimination

The deuruxolitinib mean elimination half-life is approximately 4 hrs.

Metabolism

Deuruxolitinib is primarily metabolized by CYP2C9 (76%) and CYP3A4 (21%) and to a lesser extent by CYP1A2 (3%). The two most abundant human metabolites C-21714 and C-21717, each of which accounted for approximately 5% of total drug-related AUC and both are approximately 10-fold less pharmacologically active than deuruxolitinib.

Excretion

After a single dose of radiolabeled deuruxolitinib, there was no unchanged dose recovered in either urine or feces.

Specific Populations

No clinically significant differences in the pharmacokinetics of deuruxolitinib were observed based on race [White (75%), African American (17%) and Asian (6%)], ethnicity [Hispanic or Latino (12%)], age (18-65 years), body weight (40.4-173 kg), mild to moderate renal impairment (eGFR 30-89 mL/min, MDRD), or mild to moderate hepatic impairment (Child Pugh A or B). The effect of severe renal impairment (eGFR <30 mL/min, MDRD) or severe hepatic impairment (Child Pugh C) on deuruxolitinib pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Other Drugs on Deuruxolitinib

Strong CYP3A4 and Moderate or strong CYP2C9 Inducers: Deuruxolitinib AUC decreased by 78% and C_max by 41% following concomitant use of multiple doses of 600 mg rifampin (strong CYP3A4 and moderate CYP2C9 inducer) with a single dose of 12 mg deuruxolitinib (1.5 times the approved 8 mg dose).

Strong CYP2C9 Inhibitors: Based on modeling, deuruxolitinib AUC is predicted to be increased by 200% and C_max by 25% following concomitant use of multiple dosages of a strong CYP2C9 inhibitor with a single dose of 12 mg deuruxolitinib (1.5 times the approved 8 mg dose).

Moderate CYP2C9 Inhibitors: Deuruxolitinib AUC increased by 140% and C_max by 21% following concomitant use of multiple dosages of 200 mg fluconazole (dual moderate CYP3A4 and CYP2C9 inhibitor) with a single dose of 12 mg deuruxolitinib (1.5 times the approved 8 mg dose).

Other Drugs: No clinically significant differences in deuruxolitinib pharmacokinetics were observed when used concomitantly with itraconazole (strong CYP3A4 inhibitor) or are expected with efavirenz (moderate CYP3A4 inducer).

Effect of Deuruxolitinib on Other Drugs

No clinically significant differences in the pharmacokinetics of the following drugs were observed when co-administered with deuruxolitinib: midazolam (a sensitive CYP3A4 substrate), oral contraceptives (ethinyl estradiol and levonorgestrel).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Deuruxolitinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4. Deuruxolitinib is not an inducer of CYP1A2 or CYP2B6, CYP2C8 or CYP2C19.

Transporter Systems: Deuruxolitinib is a substrate of BCRP and MDR1 but not a substrate of the uptake transporters OATP1B1 and OATP1B3. Deuruxolitinib is not an inhibitor of OATP1B1, OATP1B3 and OCT1 but is an inhibitor of BCRP, BSEP, OAT3 and MATE2-K.