Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors

Abstract

Aim: To evaluate the single-and multiple-dose pharmacokinetics of vincristine sulfate liposomes (VSLI) in patients with advanced solid tumors. Methods: In single-dose pharmacokinetic study, 16 patients were administered VSLI (1.5, 2.0, or 2.3 mg·m -2 ) through intravenous infusion. Another 6 patients receiving vincristine sulfate (VCR, 2.0 mg) were taken as the control. In multiple-dose pharmacokinetic study, 12 patients were administered VSLI (1.5 or 1.8 mg·m -2 ) through intravenous infusion weekly for 4 consecutive weeks. The plasma concentration of VSLI was determined using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Results: After intravenous infusion of the single dose of VSLI, the plasma concentrations were characterized by bi-exponential decline curves. No statistically significant differences were observed between the main pharmacokinetic parameters in the 3 dose groups. Compared with the patients receiving VCR, the patients treated with VSLI displayed an increase in the area under the plasma concentration vs time curve (AUC), and a decrease in plasma clearance rates. On the 4th cycle in the multiple-dose study, the plasma concentration of VCR in all subjects prior to the weekly administration was below the lower limit of quantification (LLOQ). The calculated pharmacokinetic parameters from the subjects in the multiple-and single-dose (1.5 mg·m -2 ) groups had no significant differences. Although the administration of liposomal VCR may significantly elevate the plasma concentration of VCR, VSLI-associated adverse events were similar to those associated with conventional VCR. Conclusion: VSLI exhibits a lower clearance and a higher AUC compared with conventional VCR. No accumulation was observed in patients exposed to VSLI for 4 consecutive weeks. VSLI was generally tolerated in the subjects. The phase II dose of VSLI may be recommended as 4 doses of 1.5 mg·m -2 for treatment of patients with advanced solid tumors.

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come

“…Clinical Studies of Marqibo. As observed in animal models, Marqibo administered to humans demonstrated a similar improvement over standard vincristine (Thomas et al, 2009;Yan et al, 2012;O'Brien et al, 2013). Indeed, higher doses of Marqibo were able to be administered to patients compared with standard vincristine (Hagemeister et al, 2013;O'Brien et al, 2013).…”

“…A single dose injection of 2.0 mg/m 2 Marqibo into patients with solid tumors demonstrated an increase in the plasma AUC and a reduction in the clearance rate of encapsulated vincristine compared with patients treated with a single 2.0 mg/m 2 dose of standard vincristine (Yan et al, 2012). However, the concentration-dependent 756 efficacy of Marqibo was not significantly different in this study when the Marqibo dose was changed to 1.5 or 2.3 mg/m 2 .…”

Vincristine sulfate liposomal injection for acute lymphoblastic leukemia

“…Patients treated with a single 2.0 mg/m 2 dose of the encapsulated VSLI formulation exhibited increased plasma AUC and decreased clearance rates compared with those treated with 2.0 mg/m 2 of conventional VCR. 34 Interestingly, variation of VSLI dose (1.5, 2.0, or 2.3 mg/m 2 ) or number of doses (1.5 or 1.8 mg/m 2 weekly for four cycles) did not significantly alter the PK of VSLI in these patients. 34 However, it should be noted that the patients in this study were Chinese and exhibited lower AUC and Cmax at a VSLI dose of 2.0 mg/m 2 compared with previous studies, 40,41 suggesting that pharmacogenomics may contribute to the PK of VSLI.…”

“…32 Data from pharmacokinetic (PK) studies revealed that clearance of liposome-encapsulated VCR was slower than that for free VCR and was thought to contribute to the higher plasma concentrations observed over a longer time period for liposomal VCR. 34,35 For example, a preclinical model comparing conventional, aqueous VCR, DSPC/cholesterol, and sphingomyelin/cholesterol liposomal formulations showed that the encapsulated drug exhibited a significantly larger area under the concentration curve (AUC) (measure of bioavailability), a longer mean plasma residence time, and a lower volume of distribution. 35 Importantly, the progressive in vivo accumulation of VCR in tissues, based on maximum concentration (Cmax), demonstrates a preference for mononuclear phagocyte system tissues such as spleen, liver, lymph nodes, and bone marrow, 36 correlating to those tissues most affected by leukemic burden.…”

Validated Spectrophotometric Method for the Estimation of Vincristine and Vinblastine

“…Vincristine and vinblastine are known, highly valuable terpenoid indole alkaloids (TIAs) from over 130 alkaloids, which were found in C. roseus. Dimeric TIA VCR has been widely used as an antitumor agent since the 1960s [1][2][3][4][5][6][7][8]. C. roseus has been used in traditional medicine in tropical and subtropical countries for the treatment of diabetes, hypertension, bleeding, scurvy, toothaches, and others from ancient time.…”