Dual effects of rifampin on the pharmacokinetics of atrasentan

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 da...

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Bibliographic Details
Published inJournal of clinical pharmacology Vol. 47; no. 4; p. 423
Main Authors Xiong, Hao, Carr, Robert A, Locke, Charles S, Katz, David A, Achari, Ramanuj, Doan, Thao T, Wang, Perry, Jankowski, James R, Sleep, Darryl J
Format Journal Article
LanguageEnglish
Published England 01.04.2007
Subjects
Adult
Area Under Curve
Atrasentan
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - biosynthesis
Drug Synergism
Endothelin A Receptor Antagonists
Enzyme Induction
Half-Life
Humans
Male
Metabolic Clearance Rate
Middle Aged
Pyrrolidines - blood
Pyrrolidines - pharmacokinetics
Rifampin - pharmacology
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Summary: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.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270007299928