Effect of ketoconazole (KET) on the pharmacokinetics (PK) of atrasentan (ABT-627, ATN)
Tong Zhu, A. Andre, I. Facey, W. Chiu, Puhan Wang, Nigel William McCracken, David A. Katz, Robert A. Carr, Thi Hoai Thu Doan, A. Allen · Journal of Clinical Oncology · 2004
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 increased most in the 2 subjects heterozygous for a low activity variant of UGT2B4; changes in ATN t1/2 and AUC did not significantly vary by UGT1A1, UGT2B15, CYP3A5, ABCB1, SLC21A6 or SLC22A2 genotype. ATN with KET was generally well tolerated. The most common AE possibly related to study drug was headache. All AEs were mild. Conclusions: KET inhibited the systemic clearance of ATN but had little effect on ATN bioavailability. Predicted steady-state ATN concentrations in the presence of KET are within the range previously shown to be well-tolerated in cancer patients. These results suggest ATN can be safely co-administered with KET, a potent inhibitor of CYP3A and Pgp. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories