RUXOLITINIB: MODE OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS

Mode of action and pharmacodynamics

Ruxolitinib phosphate – (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate – is a small-molecule tyrosine kinase inhibitor approved by the FDA for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea.99 In Europe, ruxolitinib is indicated for the treatment of adult patients with PV who are resistant to or intolerant of hydroxyurea.100 In the US, ruxolitinib is also indicated for the treatment of patients with intermediate- or high-risk MF, including primary MF, post-PV MF, and post-ET MF;99,100 ruxolitinib is approved for a similar population of patients with MF in Europe.100


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In preclinical models, ruxolitinib effectively inhibits the JAK/STAT signaling pathway as a potent and selective inhibitor of JAK1 (mean [SD] 50% inhibitory concentration [IC50], 3.3 [1.2] nM) and JAK2 (mean [SD] IC50, 2.8 [1.2] nM).101 Additionally, ruxolitinib has modest selectivity against Tyk2 (mean [SD] IC50, 19 [3.2] nM) and marked selectivity against JAK3 (mean [SD] IC50, 428 [243] nM).101 Ruxolitinib showed no significant inhibition against 26 additional kinases at concentrations 100-fold the IC50 of JAK1 and JAK2, suggesting high specificity for JAK1 and JAK2.101 The effectiveness of ruxolitinib in this pathway has also been demonstrated in cytokine-stimulated whole-blood assays in which preincubation with ruxolitinib inhibited IL-6– and thrombopoietin-mediated STAT3 phosphorylation (mean [SD] IC50, 282 [54] nM and 281 [62] nM, respectively).101

Several preclinical experiments demonstrated that ruxolitinib inhibits JAK pathway signaling of both wild-type and mutant JAK2.101 In cell lines expressing a JAK2V617F mutation, ruxolitinib effectively inhibited the phosphorylation of JAK2 downstream targets (eg, STAT3, STAT5, and ERK1/2) and induced apoptosis in a dose-dependent fashion.101 Ruxolitinib also inhibited erythroid and myeloid progenitor cell proliferation in primary cultures from healthy individuals (burst-forming unit-erythroid IC50, 407 nM; colony-forming unit-erythroid IC50, 551 nM) and patients with PV carrying the JAK2V617F mutation (burst-forming unit-erythroid IC50, 223 nM; colony-forming unit-erythroid IC50, 444 nM).101 In a murine model, ruxolitinib prolonged the survival, reduced the JAK2V617F allele burden, ameliorated splenomegaly, and normalized the elevated levels of circulating proinflammatory cytokines associated with debilitating constitutional symptoms of PV (eg, IL-6 and tumor necrosis factor-α).101

Pharmacokinetics

Ruxolitinib pharmacokinetics supports an oral route of administration.102 Ruxolitinib has a dose-proportional systemic exposure profile, with minimal accumulation following multiple doses.102 In addition, ruxolitinib is rapidly absorbed, with 95% oral bioavailability.103,104 The maximum tolerated dose of ruxolitinib was established at 25 mg twice daily and 100 mg once daily,102 and the average terminal half-life was ~3 hours.102

Ruxolitinib is metabolized primarily by the cytochrome P450 3A4 (CYP3A4) enzyme.103 In healthy human subjects, >99% of ruxolitinib doses are metabolized in a pathway that includes oxidation to single and multiple hydroxylated products, some of which then undergo O-glucuronidation.104 Unmetabolized ruxolitinib is the predominant plasma drug entity until 6 hours postdose (58%).104 Most (96%) of the total dose is excreted within 24 hours postdose, primarily via urine (74%) and feces (22%).104 Patients who receive concomitant potent CYP3A4 inhibitors may require a 50% reduction in the ruxolitinib starting dose; however, data suggest that no dosage change is required when ruxolitinib is coadministered with inducers or mild to moderate inhibitors of CYP3A4.103

Ruxolitinib dose reduction is recommended in patients with hepatic or renal impairment.99 In patients with mild and severe hepatic impairment, exposure to ruxolitinib (area under the curve) was increased because of the reduced clearance, although the magnitude of increase in ruxolitinib exposure was not correlated with the degree of hepatic impairment.105 In contrast, an increasing severity of renal impairment was associated with increased exposure to ruxolitinib’s active metabolites and consequently with increased ruxolitinib pharmacologic activity.105

RUXOLITINIB: CLINICAL OUTCOMES

Efficacy

The randomized, open-label Phase III RESPONSE registration trial demonstrated that ruxolitinib was superior to the best available therapy in adult patients with PV who were phlebotomy dependent, had splenomegaly, and were resistant to or intolerant of hydroxyurea.22 Patients were randomized to receive ruxolitinib (n=110) or the best available therapy (n=112). Pharmacological treatment in the best available therapy was chosen at the discretion of the treating physician, primarily hydroxyurea (58.9%) and IFN (11.6%); 15.2% of patients received no medication (except aspirin).22 Several limitations of the RESPONSE trial, including the open-label design and the nonstandardized determination of treatment in the best available therapy arm, may have influenced the study treatment compliance and precluded the study from comparing specific treatments with ruxolitinib. However, the study was not powered for such comparisons, and allowing treating physicians to determine the course of treatment was representative of real-world clinical settings. It is not uncommon for patients to continue treatment with hydroxyurea despite the evidence of resistance or intolerance.