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.
CITATION STYLE
Bauer, M., Zeitlinger, M., Todorut, D., Böhmdorfer, M., Müller, M., Langer, O., & Jäger, W. (2013). Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects. Pharmacology, 91(1–2), 12–19. https://doi.org/10.1159/000343243
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