Effect of ketoconazole (KET) on the pharmacokinetics (PK) of atrasentan (ABT-627, ATN)

4727 Background: ATN is an oral selective endothelin A receptor antagonist, currently in phase 3 clinical development for the treatment of hormone-refractory prostate cancer. In humans, extensive ATN metabolism is equally distributed between oxidation and glucuronidation. In vitro, CYP3A was the predominant isozyme involved in oxidative metabolism. The antifungal KET is a potent and selective CYP3A inhibitor, and is a probe of choice to determine the maximal inhibitory effect against a CYP3A-metabolized drug. Methods: To assess the effect of KET on ATN PK, a phase 1 open label study was conducted in 12 healthy subjects (11 M and 1 F; mean±SD 35±9 yrs, 80±8 kg). Subjects received ATN 10 mg PO on Days 1 and 8, and KET 200 mg PO BID from Day 4 through 10. Blood samples for ATN assay were collected predose and over 72 h after each ATN dose. Plasma concentrations of ATN were determined using a validated LC/MS/MS method. Results: ATN PK data are summarized (mean±SD; N=12) in the following table. ATN t1/2 increa...