Pharmacokinetics and safety of bromotetrandrine (BrTet, W198) after single-dose intravenous administration in healthy Chinese volunteers

Objective: To investigate the safety and pharmacokinetics of bromotetrandrine (BrTet, W198), a novel inhibitor of P‐glycoprotein (P‐gp), after single‐dose i.v. infusion in healthy Chinese volunteers. Methods: We conducted a randomized, dose‐escalating, phase I clinical study for that purpose. Thirty healthy subjects received BrTet at the doses of 10, 20 or 30 mg/m² by i.v. infusion. Plasma and urine concentrations of bromotetrandrine were determined by using a liquid chromatography–tandem mass spectrometric (LC/MS/MS) method. AUC was calculated by the trapezoidal rule extrapolation method. C_max, T_max, t_1/2α, t_1/2β, Cl and V_d were compiled from the plasma concentration–time data. Results: Bromotetrandrine was generally well tolerated at all doses. No serious or severe adverse events were found in the study. The pharmacokinetic parameters of BrTet after single i.v. infusion doses of BrTet 10, 20 and 30 mg/m² were as follows: T_max were 1·5 h in three groups, C_max were 24·79, 39·59 and 64·31 μg/L, t_1/2α were 0·37, 0·29 and 0·30 h, t_1/2β were 62·88, 56·45 and 52·20 h. AUC_0–194h were 345·83, 688·15 and 1096·28 μg h/L, Cl were 23·68, 25·69 and 25·66 L h/m², V_d were 157·73,156·96 and 140·73 L/m². In urine, the total eliminate rate of originate compound was 0·61 ± 0·19%. Conclusions: This study suggested that bromotetrandrine was well tolerated in healthy volunteers within the dose range evaluated. The pharmacokinetics parameters of bromotetrandrine indicated that the compound was rapidly distributed and accumulated in the tissues, and slowly cleared from plasma, which supported the use of BrTet for a once or twice dosing per chemotherapy cycle.