AUTHOR=Yang Fen , Jiang Min , Lu Ming , Hu Pei , Wang Hongyun , Jiang Ji 

TITLE=Pharmacokinetic Behavior of Vincristine and Safety Following Intravenous Administration of Vincristine Sulfate Liposome Injection in Chinese Patients With Malignant Lymphoma

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00991

DOI=10.3389/fphar.2018.00991

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> This phase Ia study was designed to assess the pharmacokinetic (PK) characters of free vincristine (F-VCR, refer to as non-liposomal VCR and VCR released from liposome) and total vincristine (T-VCR, the sum of both liposomal VCR and F-VCR), urinary excretion and safety of intravenous administration of vincristine sulfate liposomes injection (VSLI) in Chinese patients with malignant lymphoma and compare the results with those for conventional vincristine sulfate injection (VSI).</p><p><bold>Methods:</bold> In the phase Ia, randomized, open-label, two sequence cross-over study, patients from one group were exposed to treatment 1 including cytoxan (cyclophosphamide power injection), hydroxyrubicin (adriamycin power injection), oncovin (VSI), and prednisone tablets (standard CHOP scheme) before crossed over to treatment 2 (modified CHOP scheme in which VSI was replaced with VSLI). Patients from another group received treatments in reverse order.</p><p><bold>Results:</bold> In this phase Ia study, a total of eight subjects participated. VCR elimination from the circulation after injection of VSLI was characterized by a significantly increased maximum concentration (C<sub>max</sub>, 86.6 ng/mL) and plasma area under the plasma concentration-time curve from zero to infinity (AUC<sub>0-Inf</sub>, 222.1 ng/mL h), markedly decreased distribution volume (V<sub>z</sub>, 224.1 L) and plasma clearance (CL, 8.9 L/h) compared to lower C<sub>max</sub> (26.6 ng/mL) and AUC<sub>0-Inf</sub> (95.1 ng/mL h), larger V<sub>z</sub> (688.8 L) and CL (22.1 L/h) for VSI. The small proportion of F-VCR following infusion of VSLI in circulation was reflected by very low C<sub>max</sub> (1.8 ng/mL) and AUC<sub>0-Inf</sub> (50.5 ng/mL h). Less than 3% of the administered dose of VSLI was excreted in urine and the extent was similar to that for VSI. The elimination percentage of 40–21–14% for VSI changed to 6.2–24–39% for VSLI at intervals of 0–5, 5–13 and 13–25 h, respectively. Significant difference of toxicity between VSLI and VSI was not observed.</p><p><bold>Conclusion:</bold> VSLI exhibits higher AUC<sub>0-Inf</sub> of T-VCR, lower CL and V<sub>z</sub> compared with VSI. VSLI was well tolerated, maybe due to the markedly decreasing AUC<sub>0-Inf</sub> of F-VCR. The majority of VCR was enveloped in liposome and VCR was released gradually from liposome following injection of VSLI. Liposomal encapsulation of VCR does not alter the route and extent of VCR excretion in urine.</p>