Effect of atrasentan (ABT-627, ATN) on the pharmacokinetics (PK) of midazolam (MDZ)

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 determined using a validated LC/MS/MS method. Results: MDZ PK are summarized (mean±SD; N=15) in the following table. MDZ Cmax and AUC were bioequivalent (+/- ATN). One subject withdrew from the study after the first period (MDZ alone), and was excluded from the PK analyses. Both regimens were well tolerated. Sleepiness and headache were the most common AEs, and all AEs were mild. Conclusions: ATN had no effect on MDZ PK, indicating 10 mg QD ATN does not alter CYP3A4 activity in gut or liver. Therefore, PK interactions would not be expected between ATN and drugs metabolized by CYP3A4. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories