Journal Article

Pharmacokinetics of Single Ascending Doses of the P-Glycoprotein Inhibitor Tariquidar in Healthy Subjects

Zeitlinger, M., Böhmdorfer, M., Müller, M., Bauer, M., Todorut, D., Langer, O., Jäger, W.

2013

Overview

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.

• Publisher: S. Karger AG
• Subject: Administration, Intravenous / Adult / Area Under Curve / ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors / Blood-brain barrier / Drug therapy / Glycoproteins / Humans / Male / Middle Aged / Original Paper / Pharmacology / Quinolines - adverse effects / Quinolines - blood / Quinolines - pharmacokinetics / Young Adult