The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers.
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Shi JG, Chen X, Emm T, Scherle PA, McGee RF, Lo Y, Landman RR, McKeever EG Jr, Punwani NG, Williams WV, Yeleswaram S
The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers.
J Clin Pharmacol. 2012 Jun;52(6):809-18. doi: 10.1177/0091270011405663. Epub 2011 May 20.
- PubMed ID
- 21602517 [ View in PubMed]
- Abstract
Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC(0-infinity)) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)-6-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC(0-infinity) by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin.
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Reaction Details Details Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareRuxolitinibFluconazole The serum concentration of Ruxolitinib can be increased when it is combined with Fluconazole. RuxolitinibDexamethasone The metabolism of Ruxolitinib can be increased when combined with Dexamethasone. RuxolitinibMethimazole The metabolism of Ruxolitinib can be decreased when combined with Methimazole. RuxolitinibCarbamazepine The metabolism of Ruxolitinib can be increased when combined with Carbamazepine. RuxolitinibAmiodarone The metabolism of Ruxolitinib can be decreased when combined with Amiodarone.
