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Dual Effects of Rifampin on the Pharmacokinetics of Atrasentan

From the Departments of Clinical Pharmacokinetics (Dr Xiong, Dr Carr, Mr Jankowski), Statistics (Dr Locke), Pharmacogenetics (Dr Katz), Clinical Pharmacology (Dr Achari, Dr Doan), Drug Analysis (Dr Wang), and Oncology Drug Development (Dr Sleep), Abbott Laboratories, Abbott Park, Illinois.

The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open-label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half-life by 77% (P < .05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide-mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.

Key Words: Atrasentan • rifampin • cytochrome P450 3A • organic anion transporting polypeptide • drug interaction

Address for reprints: Hao Xiong, PhD, Abbott Laboratories, 100 Abbott Park Road, Dept. R4PK, AP13A-3, Abbott Park, IL 60064-6104; e-mail: hao.xiong{at}abbott.com.

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				E. Raichlin, A. Prasad, V. Mathew, B. Kent, D. R. Holmes Jr, G. M. Pumper, R. E. Nelson, L. O. Lerman, and A. Lerman Efficacy and Safety of Atrasentan in Patients With Cardiovascular Risk and Early Atherosclerosis Hypertension, September 1, 2008; 52(3): 522 - 528. [Abstract] [Full Text] [PDF]

				T. Gordi Comments on "Dual Effects of Rifampin on the Pharmacokinetics of Atrasentan" J. Clin. Pharmacol., September 1, 2007; 47(9): 1181 - 1181. [Full Text] [PDF]