Dataset Information

Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies.

ABSTRACT: Fulvestrant-3-boronic acid (ZB716), an oral selective estrogen receptor degrader (SERD) under clinical development, has been investigated in ADME studies to characterize its absorption, metabolism, and pharmacokinetics. ZB716 was found to have high plasma protein binding in human and animal plasma, and low intestinal mucosal permeability. ZB716 had high clearance in hepatocytes of all species tested. ZB716 was metabolized primarily by CYP2D6 and CYP3A. In human liver microsomes, ZB716 demonstrated relatively low inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (when testosterone was used as the substrate), and no inhibition of CYP2B6 and 3A4 (when midazolam was used as the substrate). In assays for enzyme activity, ZB716 induced CYP1A2, 2B6, and 3A4 in a concentration-dependent manner. Single-dose and repeated-dose pharmacokinetic studies in rats and dogs showed oral bioavailability, dose-proportional drug exposure, and drug accumulation as measured by maximum concentration and area under the concentration-time curve (AUC).

SUBMITTER: Liu J

PROVIDER: S-EPMC8400955 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: Diosgenin, charantin, and hydroxychalcone are utilized for standardization of popular antidiabetic herbal drugs Trigonella foenum-graecum L. belonging to family Fabaceae, Momordica charantia L. belonging to family Cucurbitaceae, and Cinnamomum verum J. Presl belonging to family Lauraceae. However, no reports on the bioavailability of these markers were available. The present study was undertaken to determine the bioavailability and pharmacokinetic profile of the markers and formulations containing the herbs. Methods: The pharmacokinetic profile and absolute bioavailability of the pure active markers were determined in male Wistar rats by administrating individually the doses of 1.5 mg/kg i.v. and 15 mg/kg p.o., followed by estimation of serum levels of the markers at 0, 10, 30, 60, 120, and 240 mins till 24 h time points by a validated bioanalytical HPTLC method. Two standardized antidiabetic capsule formulations containing spray dried hydroalcoholic extracts of seeds of Trigonella foenum-graecum L. (42.8 mg equivalent to 0.95%w/w of diosgenin), fresh fruits of Momordica charantia L. (21.4 mg equivalent to 0.4% w/w of charantin), and bark of Cinnamomum verum J. Presl (10.71 mg equivalent to 0.079 %w/w hydroxychalcone) were prepared. In one formulation, piperine 1.5 mg was added along with the other herbal extracts mentioned. Bioavailability and pharmacokinetic profile of these two formulations were determined in male Wistar rats through estimating serum levels of active markers diosgenin, charantin, and hydroxychalcone at 0, 10, 30, 60, 120, and 240 mins till 24 h later oral administration of the formulations (Formulation without piperine F1 and formulation with Piperine F2). Results: Plasma concentrations were found to decline mono-exponentially following intravenous administration, and the mean elimination half-life (t1/2) was observed to be 7.93, 8.21, and 4.66 h, respectively. The absolute oral bioavailability of pure markers was observed to be 9.0 ± 0.2%, 8.18 ± 0.36%, and 10.54 ± 0.52% by the dose normalization method. The oral bioavailabilities of the formulations with respect to diosgenin, charantin, and hydroxychalcone were found to be 9.78, 10.743, and 8.07%, respectively. The formulation containing piperine indicated a significant (p < 0.01) increase in the bioavailabilities of all the marker compounds. Conclusion: In conclusion, diosgenin and charantin have low bioavailabilities as compared to hydroxychalcone. The bioavailabilities of all the three marker compounds can be increased exponentially with the addition of piperine.

Project description:BackgroundTargeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells.MethodsIn order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059.ResultsGenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile.ConclusionGenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

Dataset Information

Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets