title: Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects.
abstract: We assessed the pharmacokinetics (PK), tolerability and safety of tariquidar (TQD), a P-glycoprotein (Pgp) inhibitor, after intravenous administration of single ascending doses. Employed doses were up to 4-fold higher than in previous clinical trials in cancer patients and are capable of inhibiting Pgp at the blood-brain barrier. Fifteen male healthy volunteers were randomized to receive single intravenous doses of TQD at 4, 6 or 8 mg/kg body weight and underwent blood sampling for over 24 h. TQD concentrations were determined in plasma samples with high-performance liquid chromatography mass spectrometry. No dose-limiting toxicities of TQD were observed. The area under the plasma concentration-time curve from start until 24 h after the end of infusion was positively correlated with an administered TQD dose (r = 0.8981, p < 0.0001). Moreover, we found a positive correlation for volume of distribution at steady state (r = 0.7129, p = 0.0004) with TQD dose. Dose dependency of volume of distribution at steady state points to non-linear PK of TQD, which was in all likelihood caused by transporter saturation at high TQD doses. Acceptable safety and tolerability as well as dose-linear increases in plasma exposure support the future use of TQD at doses up to 8 mg/kg to inhibit Pgp at the human blood-brain barrier.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Bauer
authors.forename: M
authors.initials: M
authors.lastname: Zeitlinger
authors.forename: D
authors.initials: D
authors.lastname: Todorut
authors.forename: M
authors.initials: M
authors.lastname: Böhmdorfer
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: O
authors.initials: O
authors.lastname: Langer
authors.forename: W
authors.initials: W
authors.lastname: Jäger
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D061605:Administration, Intravenous; D000328:Adult; D019540:Area Under Curve; D006801:Humans; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; C402343:tariquidar