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.

Fig. 1

Mean (±SD) concentration-time curves of TQD in plasma for the 4, 6 and 8 mg/kg dose groups (n=5 per dose group). For comparison, previously published data from a 2 mg/kg dose group (n=5) is also shown [14].

Fig. 2

Scatter plots and linear regression of the pharmacokinetic parameters AUC_0-n (a) and V_SS (b) versus the administered dose. For comparison, the 2 mg/kg dose group data, depicted as open squares, is also shown [14].