ABSTRACT
PURPOSE: Investigation of the impact of co-medication on the plasma levels of curcumin and tetrahydrocurcumin (THC) in cancer patients and a comparison of the pharmacokinetics of curcumin and plasma levels of THC between cancer patients and healthy individuals following intravenous infusion of Lipocurc™ (liposomal curcumin). METHODS: Correlation analysis was used to determine the impact of co-medication on infusion rate normalized plasma levels of curcumin and THC in cancer patients and to compare the plasma levels of curcumin and THC at different infusion rates between cancer patients and healthy individuals. In vitro hepatocyte and red blood cell distribution experiments were conducted with Lipocurc™ to support clinical findings. Plasma concentration time data were analyzed by the non-compartmental method to determine and compare the pharmacokinetic parameters of curcumin in cancer patients and healthy individuals. RESULTS: Of 44 co-medications studied, three medications targeting the renin-angiotensin system, Lisinopril, Ramipril, and Valsartan elevated plasma levels of curcumin and THC in three cancer patients infused with Lipocurc™. Cell distribution experiments indicated that the disposition of curcumin in red blood cells may be a target for elevation of the plasma levels of curcumin. Plasma levels of curcumin in cancer patients increased to a greater extent with increased infusion rate compared to healthy individuals. Upon termination of infusion, the elimination phase for curcumin was shorter with a shorter terminal half-life and smaller volume of distribution for curcumin in cancer patients compared to healthy individuals. CONCLUSION: Either co-medications or health status, or both, can impact the pharmacokinetics of curcumin infusion (as Lipocurc™) in cancer patients.
Subject(s)
Curcumin/analogs & derivatives , Curcumin/pharmacokinetics , Erythrocytes/metabolism , Hepatocytes/metabolism , Liposomes/administration & dosage , Neoplasms/drug therapy , Animals , Case-Control Studies , Cells, Cultured , Curcumin/administration & dosage , Curcumin/chemistry , Dogs , Drug Therapy, Combination , Erythrocytes/drug effects , Healthy Volunteers , Hepatocytes/drug effects , Humans , Infusions, Intravenous , Male , Neoplasms/metabolism , Tissue DistributionABSTRACT
PURPOSE: This study was conducted to investigate the safety and tolerability of increasing doses of liposomal curcumin in patients with metastatic cancer. Investigations of anti-tumor activity and of the pharmacokinetics of curcumin were secondary objectives. METHODS: In this phase I, single-center, open-label study in patients with metastatic tumors, liposomal curcumin was administered as a weekly intravenous infusion for 8 weeks. Dose escalation was started at 100 mg/m2 over 8 h and the dose increased to 300 mg/m2 over 6 h. RESULTS: 32 patients were treated. No dose-limiting toxicity was observed in 26 patients at doses between 100 and 300 mg/m2 over 8 h. Of six patients receiving 300 mg/m2 over 6 h, one patient developed hemolysis, and three other patients experienced hemoglobin decreases > 2 g/dL without signs of hemolysis. Pharmacokinetic analyses revealed stable curcumin plasma concentrations during infusion followed by rapid declines to undetectable levels after the infusion. Anti-tumor activity by RECIST V1.1 was not detected. Significant tumor marker responses and transient clinical benefit were observed in two patients. CONCLUSION: 300 mg/m2 liposomal curcumin over 6 h was the maximum tolerated dose in these heavily pretreated patients, and is the recommended starting dose for anti-cancer trials.
