Abstract

BACKGROUND: Selenite is a radiosensitizer and inhibitor of androgen receptor expression and function. In a phase I study (NCT02184533) in 15 subjects with metastatic cancer receiving daily oral sodium selenite with palliative radiation therapy, disease stabilization was observed, as evidenced by tumor regression, marked reduction in pain symptoms, and decreased prostate-specific antigen levels (only patients with castrate-resistant prostate cancer).OBJECTIVE: The aim of this work was to characterize the pharmacokinetics of selenite to suggest dosing strategies and to propose a study design for further investigation.METHODS: Withselenium plasma concentrations obtained from five dosing cohorts (5.5, 11, 16.5, 33, and 49.5 mg), a population pharmacokinetic model was constructed using NONMEM. The model described externally administered selenite (inorganic) with a baseline component for endogenous selenium levels. Using the pharmacokinetic model, simulations were performed to suggest dosing regimens that achieved in vitro target selenite levels, and optimal pharmacokinetic sampling times for a subsequent study were proposed using PopED.RESULTS: A one-compartment model characterized selenite pharmacokinetics. Parameter estimates were absorption rate constant (0.64h-1), apparent clearance (1.58L/h), apparent volume of distribution (42.3L), and baseline selenium amount (5270mug). A logarithmic function characterized the inverse relationship between dose level and bioavailability. Four regimens to reach in vitro target selenite levels were proposed: 33mg daily, 16.5mg twice daily (BID), 11mg BID, and 5.5mg thrice daily (TID). Optimal sampling times were 1, 2, 6, and 24h.DISCUSSION: The population model described the pharmacokinetic data well. Three regimens (33 mg daily, 11 mg BID, 5.5 mg TID) achieved in vitro target selenite levels after one dose. The model and optimal sampling times may inform future studies evaluating the efficacy of selenite for metastatic cancer treatment.

View details for DOI 10.1007/s40268-021-00340-9

View details for PubMedID 33866531