Inter-Species Pharmacokinetic Modeling and Scaling for Drug Repurposing of Pyronaridine and Artesunate.

Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (Vss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × Wb) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials.

Sex, age, and species differences of perfluorooctanoic acid modeled by flow- versus permeability-limited physiologically-based pharmacokinetic models.

This study aimed to investigate sex, age, and species differences of perfluorooctanoic acid (PFOA) using physiologically-based pharmacokinetic (PBPK) models in rats and humans. PBPK models were generally developed as either flow- or permeability-limited models. The flow-limited model is cost-effective and allows for human PK prediction through simple allometric scaling, while the permeability-limited model can incorporate detailed information on the disposition process through in vitro-in vivo extrapolation (IVIVE). PFOA was administered via oral or intravenous administration with 5 mg/kg in male and female rats of different ages and the data was used to develop the PBPK models. Our results showed that both models successfully captured sex differences in rats, while only the flow-limited model with male rats and the permeability-limited model with both male and female rats provided comparable predictions in the human clinical study. More than the flow-limited model, the permeability-limited model effectively explained sex differences in rats and species differences through IVIVE. Additionally, the ontogeny-based mechanistic description of PFOA disposition enabled the interpretation of age- and sex-dependent pharmacokinetics. Although the flow-limited PBPK model lacked mechanistic interpretability compared to the permeability-limited model, it demonstrated reliable human prediction through simple allometric scaling. In conclusion, the permeability PBPK model could interpret age, sex, and species differences and it could improve the accuracy of human prediction.

Physiologically-based pharmacokinetic model for evaluating gender-specific exposures of N-nitrosodimethylamine (NDMA).

N-nitrosodimethylamine (NDMA) is classified as a human carcinogen and could be produced by both natural and industrial processes. Although its toxicity and histopathology have been well-studied in animal species, there is insufficient data on the blood and tissue exposures that can be correlated with the toxicity of NDMA. The purpose of this study was to evaluate gender-specific pharmacokinetics/toxicokinetics (PKs/TKs), tissue distribution, and excretion after the oral administration of three different doses of NDMA in rats using a physiologically-based pharmacokinetic (PBPK) model. The major target tissues for developing the PBPK model and evaluating dose metrics of NDMA included blood, gastrointestinal (GI) tract, liver, kidney, lung, heart, and brain. The predictive performance of the model was validated using sensitivity analysis, (average) fold error, and visual inspection of observations versus predictions. Then, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty of the single model predictions. The developed PBPK model was applied for the exposure simulation of daily oral NDMA to estimate blood concentration ranges affecting health effects following acute-duration (≤ 14 days), intermediate-duration (15-364 days), and chronic-duration (≥ 365 days) intakes. The results of the study could be used as a scientific basis for interpreting the correlation between in vivo exposures and toxicological effects of NDMA.

Parent-Metabolite Pharmacokinetic Modeling of Formononetin and Its Active Metabolites in Rats after Oral Administration of Formononetin Formulations.

Formononetin is a major isoflavone contained in propolis and is reported to exhibit various pharmacological effects. However, the use of formononetin in pharmaceutical industry is limited due to its low bioavailability and solubility. There had been several efforts on formononetin formulation development, but further study is required to acquire optimal formulation. The aim of this study is to conduct pharmacokinetic (PK) evaluations after the oral administration of three formononetin formulations (20 mg/kg) in male Sprague Dawley rats. Then, a parent-metabolite PK model for formononetin was developed and evaluated for the first time. To do this, a simultaneous analysis method for formononetin and its active metabolites, daidzein, dihydrodaidzein and equol in rat plasma was developed using ultra-performance liquid chromatography tandem mass spectrometry. The separation was performed using a gradient elution of water and acetonitrile and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 µm particle size) at a temperature of 30 ± 5 °C. The simultaneous analytical method developed in this study was validated according to international guidance and was successfully applied for the pharmacokinetic study. The time-plasma concentrations of formononetin and daidzein were well described by a two-compartment model combined with a metabolite compartment. Additionally, plasma protein binding assay was conducted in male rat plasma. The findings from the study could be used as a fundamental for the future development of formononetin as a pharmaceutical product.

Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.

Gold Nanowire Bundles Grown Radially Outward from Silicon Micropillars.

One-dimensional (1D) micro- and nanostructures have become increasingly popular because of their tremendous prospect in various applications. While the design and fabrication of these structures from a single component in two-dimensional (2D) arrays is common, the attainment of hierarchical three-dimensional (3D) architectures made up of multicomponent one-dimensional structures is rare. Herein we report, for the first time, the lateral growth of gold nanowires from the sidewalls of substrate grown silicon micropillars to form a unique "wire-on-pillar" architecture. Unlike zero-dimensional (0D) point-like, 1D linear, and 2D planar Au structures, the obtained 3D "wire-on-pillar" Au architecture provides abundant hotspots between adjacent Au wires, which led to remarkably high surface-enhanced Raman scattering (SERS) signals.