butyl ether (MTBE) with 13 C 4 -labeled ruxolitinib as the internal standard, the reconstituted extracts were separated by high-performance liquid chromatography (HPLC) over a Phenomenex (Torrance, California) Synergi 4Polar-RP 80A (30 2-mm) column LY450139  under isocratic conditions. The analyte was quantitated by MS/MS using a Sciex API-3000 mass spectrometer (Applied Biosystems, Foster City, California) operating in positive ion multiple-reaction monitoring (MRM) mode, monitoring the transition of the m/z 307.3 precursor 2 J Clin Pharmacol   Downloaded from jcp.sagepub at Bobst Library, New York University on March 7, 2012 3  THE EFFECT OF CYP3A4 INHIBITION Evaluation of CYP3A4 Inhibition/Induction on Ruxolitinib PK/PD Study A:

Effect of CYP3A4 Inhibition on Single-Dose Ruxolitinib PK/PD Study B: Effect of CYP3A4 Induction on Single-Dose Ruxolitinib PK/PD Ketoconazole Coadministration (Cohort 1, n=16) Erythromycin Coadministration (Cohort 2, n=15) Rifampin Coadministration (n=12) 10 mg ruxolitinib (alone, n=16) 200 mg bid ketoconazole 10 mg rux Fostamatinib
sulting in only a 10% decrease in the overall PD activity. This apparent PK/PD he Janus kinase family of protein tyrosine kinases (JAKs) activates a number of downstream path- ways implicated in proliferation and survival of cells, including the STATs (signal transducers and activators of transcription), a family of latent transcription fac- tors. 1 Dysregulated JAK-STAT activity has been identi- fied in patients with myeloproliferative neoplasms, 2,3 a group of diseases of bone marrow without specifi- cally approved treatment. Ruxolitinib (INCB018424 phosphate) is a potent and selective small-molecule From the Incyte Corporation, Wilmington, Delaware.

Submitted for publication December 7, 2010; revised version accepted January 25, 2011. Address for correspondence: Jack G. Shi, PhD, Incyte Corporation, Experimental Station, Building E400, Wilmington, DE 19880; :  DOI: 10.1177/0091270011405663 J Clin order Cidofovir Pharmacol xxxx;xx:x-x 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.

Keywords: ruxolitinib; INCB018424; JAK; drug interaction; pharmacokinetics Journal of Clinical Pharmacology, XXXX;XX:xxx-xxx 2011 The Author(s) inhibitor of JAK1&2 4 that is first in its class undergoing pivotal phase 3 trials for treatments of myelofibrosis (MF) and advanced polycythemia vera (PV), after dem- onstrating safety and efficacy in patients with MF and PV in 2 phase 2 trials. 5,6 In 2 prior clinical studies conducted to evaluate single- and multiple-dose pharmacokinetics in healthy adult volunteers, 7 ruxolitinib supplier Cidofovir demonstrated good oral bioavailability with rapid absorption, typically attain- ing peak plasma concentrations within 2 hours post- dose.

Ruxolitinib exhibited a low oral dose clearance (~19 L/h) that was dose independent over the range of 5 to 200 mg, as well as a small apparent oral dose vol- ume of distribution (~80 L). Minimal drug accumulation was observed following multiple bid dosing of ruxoli- tinib, consistent with the relatively short elimination half-life (~3 hours). The systemic humorism elimination of rux- olitinib is largely via metabolism based on negligible renal excretion of the parent drug and presence of mul- tiple metabolites in plasma. A total of 8 metabolites in human plasma were identified, characterized, and their respective reference standards synthesized.