netic plasma samples were assayed by a validated, good laboratory practice (GLP), liquid chromatography/tandem mass spectrometry (LC/ MS/MS) method at Incyte Corporation (Wilmington, Delaware). Plasma concentrations of INCB018424 1646 J Clin Pharmacol 2011;51:1644-1654 Downloaded from jcp.sagepub at Bobst Library, New York University on March 7, 2012 4  PK, PD, AND SAFETY OF ORALLY DOSED INCB018424 phenformin PHOSPHATE were determined following a liquid/liquid extrac- tion procedure using methyl-t-butyl ether (MTBE) with 13 C 4 -labeled INCB018424 as the internal stand- ard. Chromatography was performed with a Phenomenex Synergi 4Polar-RP 80A (30 2 mm) column (Phenomenex, Torrance, California) under isocratic conditions and a mobile phase consisting of 55% acetonitrile and 45% 2mM ammonium ace- tate aqueous solution.

MS/MS analysis was per- formed using a positive Turbo IonSpray interface on a Sciex API-3sm based on the identification of multiple metabolites coupled with negligible renal clearance in all animal species studied (data on file). In vitro studies indicate that Apixaban  INCB018424 is metabo- lized primarily by the cytochrome P450 enzyme, CYP3A4. This report summarizes the oral dose phar- macokinetics (PK), pharmacodynamics (PD), safety, and tolerability of INCB018424 phosphate in healthy adult volunteers and the utility of using a target- specific biomarker in the identification of doses of INCB018424 for further development. METHODS Study Population Men and women, 18 to 55 years of age, with a body mass index between 18 and 30 kg/m 2 were eligible for participation in the studies if they were judged to be in good health based on their medical history and physical examinations, including vital signs, elec- trocardiogram, and clinical laboratory test results. Women of childbearing potential enrolled in these studies were determined to be in a nongravid state and had agreed to take appropriate precautions (with at least 99% certainty) to avoid pregnancy from screening through follow-up.

Applicants with hemoglobin levels and white blood and platelet counts below the lower reference limit for the param- eters were excluded. Nontudy medications were not allowed for 7, 14, and 30 days, for over-the- counter, prescription, and investigational drugs,  FTY720 162359-56-0 respectively, prior to the first dose of study medica- tion until the completion of study, unless deemed necessary and acceptable by the investigator. Use of any medications known to affect cytochrome P450 enzymes or P-glycoprotein activity was prohibited within 30 days or 5 half-lives (whichever was longer) prior to the study start and throughout the study. Study Design An overview for the 2 studies evaluating INCB018424 PK, PD, and safety in healthy adult participants is PHARMACOKINETICS AND PHARMACODYNAMICS INCB018424 PK/PD/Safety Studies in Healthy Adult Volunteers Single-Dose Escalation Study Multiple-Dose Escalation Study Design: randomized, placebo-controlled Design: randomized, placebo-controlled 2-cohort, multi-sequence/period, 6 doses 6-cohort.

1 dose per cohort, 5 doses No. of subjects enrolled/completed: 23/18 No.of subjects FTY720 Src-bcr-Abl inhibitor enrolled/completed: 71/68 Food Effect Study Design: randomized, open-label 2-sequence & period, cross-over No. of subjects senrolled/completed: 12/12 Figure 1. An overview of the study design. The 12 volunteers who par- ticipated in the food effect evaluation had completed the single-dose escalation study. PD, pharmacodynamics; PK, pharmacokinetics. provided in Figure 1. Both studies were conducted at Quintiles Phase I Services (Overland Park, Kansas) in full accordance with the Declaration of Helsinki; the Good Clinical Practice: Consolidated Guideline , approved by the International Conference on Harmoni- zation; good clinical practices as smallpox vaccine  required by and described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56, 312 subpart D, and 314; and stand- ard operating procedures (SOPs) for clinical investi- gation and local laws regarding the protection