Abstract
4725 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 metabolizm is equally distributed between oxidation (CYP3A) and glucuronidation. In vitro, ATN inhibits CYP3A with an IC50 of ∼3 μM (15-fold the mean plasma Cmax for 10 mg/d ATN). The sedative MDZ is extensively metabolized by CYP3A in both gut and liver. MDZ plasma concentrations are sensitive to CYP3A inhibition; MDZ is an FDA-recommended probe CYP3A4 substrate. Methods: To assess the effect of ATN on MDZ PK, a phase 1 double-blind, randomized, two-period crossover study was conducted in 16 healthy subjects (13 M and 3 F; mean±SD 41±11 yrs, 78±13 kg). Subjects received ATN 10 mg or placebo PO QD from Day 1 through 7; in both regimens MDZ was given on Day 4 (1 mg IV) and Day 6 (5 mg PO). Blood samples for MDZ assay were collected predose and over 48 h after each MDZ dose. Plasma concentrations of MDZ were de...
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