A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors

Abstract

Background: Ursolic acid is a promising anticancer agent. The current study aims to evaluate the single-and multiple-dose pharmacokinetics (PK) as well as the safety of ursolic acid nanoliposomes (UANL) in healthy volunteers and in patients with advanced solid tumors. Methods: Twenty-four healthy volunteers in the single-dose PK study were divided into three different groups, which received 37, 74, and 98 mg/m 2 of UANL. Eight patients in the multiple-dose PK study were administered with 74 mg/m 2 of UANL daily for 14 days. The UA plasma concentrations were determined using ultra-performance liquid chromatograph-tandem mass spectrometry. Results:The plasma concentration profiles of all subjects were characterized by a biexponential decline after infusion. The mean peak plasma concentration (C max ) increased linearly as a function of the dose (r = 0.999). The mean area under the plasma concentration-time curve (AUC) from 0 to 16 hours also increased proportionally with dose escalation (r = 0.998). However, the clearance was constant over the specific dose interval. In the multiple-dose PK study, the trough and average concentrations remained low. The mean AUC, half-life, C max , time to C max , and the volume of distribution on the first day were similar to those on the last day. All subjects tolerated the treatments well. Most UANL-associated adverse events varied from mild to moderate. Conclusions: UANL exhibits relatively linear PK behavior with dose levels from 37 mg/m 2 to 98 mg/m 2 . No drug accumulation was observed with repeated doses of UANL. The intravenous infusion of UANL was well tolerated by healthy volunteers and patients with advanced tumors.

Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma

“…In order to investigate whether UA may improve cell susceptibility to DXR, the dose of UA in the combination experiments was adjusted to 10 μM for synovial sarcoma cells and 15 μM for leiomyosarcoma cells, because at these concentrations UA had a similar effect on cell viability and apoptosis in each of the respective cell lines according to their IC 50 values (Figs 1 and 2 ). A phase I pharmacokinetic study of UA nanoliposomes showed that plasma concentrations of this compound can reach up to 7.6 μM [ 27 ], which similar to the concentrations used here. The concentrations of DXR used in our study (0.1–10 μM) are typical for studies with doxorubicin-resistant or -insensitive cell lines and have been used by us [ 26 ] and others in similar in vitro studies performed with STS cell lines [ 28 , 29 ] as well as with other types of cancer cells [ 30 ] and can be clinically achieved in human plasma [ 31 ].…”

Resveratrol and P-glycoprotein Inhibitors Enhance the Anti-Skin Cancer Effects of Ursolic Acid

“…In addition, UA is reasonably tolerated in humans, and can achieve concentrations as high as 7.57 μM in the serum when supplied intravenously in nanoliposomes (49). We suggest use of UA in addition to approved P-gp inhibitors may be a valuable method to prevent or reverse tumor formation in P-gp-expressing human tumors.…”

Potential Protective Effects of Ursolic Acid against Gamma Irradiation-Induced Damage Are Mediated through the Modulation of Diverse Inflammatory Mediators

“…Several phase I clinical trials have been conducted to evaluate the safety, tolerance and antitumor activity of intravenously administrated UAL. It was found that UAL was tolerable with manageable levels of toxicity, and could potentially improve remission rates in patients (Wang et al, 2013, 2015; Zhu et al, 2013; Qian et al, 2015). …”