The AAPS Journal

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice

The orally available novel small molecule SHetA2 is the lead sulfur-containing heteroarotinoid that selectively inhibits cancer cells over normal cells, and is currently under clinical development for anticancer treatment and cancer prevention. The objective of this study was to assess and characterize the tissue distribution of SHetA2 in tumor-bearing mice by developing a physiologically based pharmacokinetic (PBPK) model. An orthotopic SKOV3 ovarian cancer xenograft mouse model was used to most accurately mimic the ovarian cancer tumor microenvironment in the peritoneal cavity. SHetA2 concentrations in plasma and 14 different tissues were measured at various time points after a single intravenous dose of 10 mg/kg and oral dose of 60 mg/kg, and these data were used to develop a whole-body PBPK model. SHetA2 exhibited a multi-exponential plasma concentration decline with an elimination half-life of 4.5 h. Rapid and extensive tissue distribution, which was best described by a perfusion rate-limited model, was observed with the tissue-to-plasma partition coefficients (k

Tumor-Infiltration Mimicking Model of Contaminated Ovarian Tissue as an Innovative Platform for Advanced Cancer Research

The development of advanced preclinical models is crucial for the evaluation and validation of novel therapeutic strategies in oncology. Three-dimensional (3D) microtumor models, which incorporate both cancer and stromal cells within biomimetic hydrogels, have emerged as powerful tools that more accurately replicate the complex tumor microenvironment compared to traditional two-dimensional (2D) cell culture systems. In this context, our study aims to develop 3D microtumor models by integrating cancer and stromal cells within an extracellular-matrix-mimetic hydrogel, as a physiologically accurate microtumor model that can serve as an innovative platform for advanced cancer research and drug screening. Microtumors composed of varying ratios of leukemia cells (HL-60) to healthy ovarian stromal cells (SCs) (1:1, 1:10, 1:100, or 1:1000) were encapsulated in PEGylated fibrin hydrogel and cultured for 5 days. The proliferation and dynamics of cancerous and healthy cell populations were evaluated using CD43/Ki67 immunofluorescence double staining. Our findings indicate that tumor development and malignancy progression can be influenced by adjusting cell culture ratios and incubation time. Notably, the HL-60:SCs ratio of 1:100 closely replicated leukemia cell invasion in ovarian tissue, demonstrating detectable malignancy on the third and fifth days without significant changes in total cell density dynamics. This 3D leukemia microtumor model offers superior physiological relevance compared to traditional 2D in vitro assays and shows promising potential for applications in cellular analysis and drug screening.

Pharmacodynamics of Cyclin D1 Degradation in Ovarian Cancer Xenografts with Repeated Oral SHetA2 Dosing

AbstractSHetA2 is a promising, orally active small molecule with anticancer properties that target heat shock proteins. In this study, we aimed to investigate the pharmacodynamic (PD) effects of SHetA2 using preclinical in vitro and in vivo models of ovarian cancer and establish a physiologically based pharmacokinetic (PBPK)/PD model to describe their relationships with SHetA2 concentrations in mice. We found that daily oral administration of 60 mg/kg SHetA2 for 7 days resulted in consistent plasma PK and tissue distribution, achieving tumor drug concentrations required for growth inhibition in ovarian cancer cell lines. SHetA2 effectively induced cyclin D1 degradation in cancer cells in a dose-dependent manner, with up to 70% reduction observed and an IC50 of 4~5 µM. We identified cyclin D1 as a potential PD marker for SHetA2, based on a well-correlated time profile with SHetA2 PK. Additionally, we examined circulating levels of ccK18 as a non-invasive PD marker for SHetA2-induced apoptotic activity and found it unsuitable due to high variability. Using a PBPK/PD model, we depicted SHetA2 levels and their promoting effects on cyclin D1 degradation in tumors following multiple oral doses. The model suggested that twice-daily dosing regimens would be effective for sustained reduction in cyclin D1 protein. Our study provides valuable insights into the PK/PD of SHetA2, facilitating future clinical trial designs and dosing schedules.

PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts-a hematotoxicity marker-and serum creatinine-a nephrotoxicity marker-were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m