The objective of this study was to estimate the population pharmacokinetics of voriconazole, to identify the factors influencing voriconazole pharmacokinetics and to identify optimal dosage regimens for attaining target pharmacokinetic/pharmacodynamic indices against Aspergillus and Candida infections in patients with invasive fungal infections (IFIs). To prospectively quantify the relationships between the pharmacokinetic parameters of voriconazole and covariates, a population pharmacokinetic analysis was conducted on pooled data from 406 samples taken from 151 patients with IFIs. Voriconazole plasma concentrations were measured by HPLC. The following covariates were tested: demographic factors, laboratory data, concomitant medications and CYP2C19 genotype. Monte Carlo simulation was used to evaluate the effectiveness of the currently recommended dosage regimen and to design an optimized pharmacodynamic dosage strategy for voriconazole. The data were appropriately fit by a one-compartment model with first-order absorption and elimination. The voriconazole clearance (CL) was 6.95 L/h, the volume of distribution (V) was 200 L and the oral bioavailability (F) was 89.5%. CL was significantly associated with age, the serum concentration of alkaline phosphatase and the CYP2C19 genotype. Based on the results of the Monte Carlo stimulation, we concluded that Aspergillus infections could be treated effectively with 200 mg of voriconazole administered intravenously or orally twice daily and that Candida infections could be treated with 300 mg administered orally twice daily or with 200 mg administered intravenously twice daily. This study showed that optimal voriconazole dosage regimens could be determined successfully with prospective population pharmacokinetic analyses and Monte Carlo simulations.

Emerging evidence indicates that breast cancer-initiating cells (CICs) are relatively resistant to radiotherapy; however, the critical mechanisms determining breast CIC resistance to radiation remain elusive. In the present study, a subpopulation of cells displaying characteristics generally attributed to stem cells was identified within the breast cancer cell line MCF-7. This subpopulation displays cancer stem cell features characterized by overexpression of embryonic stem cell markers, high tumorigenic potential following transplantation into BALB/c-nu mice, self-renewal capacity and resistance to ionizing radiation (IR). Moreover, glucose‑regulated protein 78KD (GRP78), which was found to play a crucial role in stem cell oncogenesis, was also shown to be overexpressed in this subpopulation. GRP78 is required for the cancer stem-like subpopulation cell resistance to IR, as knockdown of this gene augments the effects of IR, while overexpression of GRP78 increases the radiation resistance of the subpopulation to IR. These findings indicate that GRP78 acts as a potential therapeutic target aimed at tumor-generating subsets of breast cancer cells.