Pharmacokinetics of panaxatrol disuccinate sodium, a novel anti-cancer drug from Panax notoginseng, in healthy volunteers and patients with advanced solid tumors
Abstract
Aim: To evaluate single-dose and multiple-dose pharmacokinetics of panaxatrol disuccinate sodium in healthy volunteers and patients with advanced solid tumors.
Methods:<.strong> In the single-dose pharmacokinetic study, 27 healthy volunteers received panaxatrol disuccinate sodium in three doses (70, 100, and 140 mg·m−2). In the multiple-dose pharmacokinetic study, Panaxatrol disuccinate sodium was administered to 8 patients at 100 mg·m−2 daily in a 30-day continuous intravenous injection. Determination of the panaxatrol disuccinate sodium plasma concentration was performed by an LC-MS method. The pharmacokinetic analysis system — Drug and Statistics (DAS) — was applied to assess plasma panaxatrol disuccinate sodium concentration-time data.
Results: After a single intravenous dose of 70, 100, or 140 mg·m−2 was administered to subjects, panaxatrol disuccinate sodium distributed broadly, and the plasma concentration of panaxatrol disuccinate sodium declined rapidly. No significant differences were observed in the main pharmacokinetic parameters among the three dosing groups, including AUC0–t, MRT0–t, VRT0–t, t1/2Z, CLz/F, Vz/F, and C0 (P>0.05). In the multiple-dose pharmacokinetic study, the mean steady-state peak concentration (Cmax), trough concentration (Cmin), average concentration (Cav), mean steady state AUC (AUCss) and the degree of fluctuation were 13.96±15.48 mg·L−1, 0.18±0.29 mg·L−1, 0.15±0.29 mg·L−1, 3.58±6.94 mg·L−1·h, and 148.00±117.18, respectively. At any given dose of panaxatrol disuccinate sodium, interindividual variability in the pharmacokinetic parameters was obvious.
Conclusion: The effect of the dose level on single-dose pharmacokinetics of panaxatrol disuccinate sodium was not significant. No accumulation was observed with exposure to 100 mg·m−2 panaxatrol disuccinate sodium in the 30-day continuous intravenous injection. All subjects were evaluated for tolerability throughout the study. Thus, the phase II dose of panaxatrol disuccinate sodium may be considered to be 100 mg·m−2 for a 30-day continuous intravenous injection to treat patients with advanced solid tumors.
Keywords:
Methods:<.strong> In the single-dose pharmacokinetic study, 27 healthy volunteers received panaxatrol disuccinate sodium in three doses (70, 100, and 140 mg·m−2). In the multiple-dose pharmacokinetic study, Panaxatrol disuccinate sodium was administered to 8 patients at 100 mg·m−2 daily in a 30-day continuous intravenous injection. Determination of the panaxatrol disuccinate sodium plasma concentration was performed by an LC-MS method. The pharmacokinetic analysis system — Drug and Statistics (DAS) — was applied to assess plasma panaxatrol disuccinate sodium concentration-time data.
Results: After a single intravenous dose of 70, 100, or 140 mg·m−2 was administered to subjects, panaxatrol disuccinate sodium distributed broadly, and the plasma concentration of panaxatrol disuccinate sodium declined rapidly. No significant differences were observed in the main pharmacokinetic parameters among the three dosing groups, including AUC0–t, MRT0–t, VRT0–t, t1/2Z, CLz/F, Vz/F, and C0 (P>0.05). In the multiple-dose pharmacokinetic study, the mean steady-state peak concentration (Cmax), trough concentration (Cmin), average concentration (Cav), mean steady state AUC (AUCss) and the degree of fluctuation were 13.96±15.48 mg·L−1, 0.18±0.29 mg·L−1, 0.15±0.29 mg·L−1, 3.58±6.94 mg·L−1·h, and 148.00±117.18, respectively. At any given dose of panaxatrol disuccinate sodium, interindividual variability in the pharmacokinetic parameters was obvious.
Conclusion: The effect of the dose level on single-dose pharmacokinetics of panaxatrol disuccinate sodium was not significant. No accumulation was observed with exposure to 100 mg·m−2 panaxatrol disuccinate sodium in the 30-day continuous intravenous injection. All subjects were evaluated for tolerability throughout the study. Thus, the phase II dose of panaxatrol disuccinate sodium may be considered to be 100 mg·m−2 for a 30-day continuous intravenous injection to treat patients with advanced solid tumors.