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Hemodialysis (HD) is a method used to remove biogenic substances or blood components that cause disease and some drugs used by patients to treat their diseases. Therefore, dosing schedule must be planned according to HD clearance (CL HD ) when medical treatment is provided to patients receiving HD. We aimed to clarify the physical properties (eg, octanol-water partition coefficient and molecular electronegativity) or pharmacokinetic parameters (eg, volume of distribution) of compounds affecting CL HD and to construct a mathematical model to predict CL HD . The analysis covered individual CL HD data for nine compounds from the literature. The molecular descriptors which are physical properties or pharmacokinetic parameters were calculated using the structural formula of each compound, and searched for factors related to CL HD among the calculated 148 molecular descriptors. Nonlinear mixed-effects model analysis with CL HD as objective variable and molecular descriptors as explanatory variable was conducted to examine the factor affecting CL HD and develop a model for predicting CL HD . The logarithm of the brain/blood partition coefficient was detected as a factor affecting CL HD . The predictive accuracy of CL HD using the constructed mathematical model with the logarithm of the brain/blood partition coefficient as explanatory variable was adequate., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population PK analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 white) under strictly controlled trial conditions with regulated meals and a single lot of the drug. We found that CYP2C9 genotype and lean body mass were statistically significant predictors of clearance and volume of distribution, respectively. A statistical significant difference in the PK parameters between ethnic groups could not be identified. Simulations using PK/PD models showed that CYP2C9 genotype is the factor that affects the PDs of meloxicam. The genetic polymorphisms highlighted in this study would be beneficial for conducting clinical trials in East Asians with similar genetic backgrounds. [ABSTRACT FROM AUTHOR]

Aims To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal and noncompetitive inhibitor of type I and type II 5α-reductases, (–)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers. Methods In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (≥ 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input. Results Maximum plasma concentration (C max ) and the area under the concentration–time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8–12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses... [ABSTRACT FROM AUTHOR]

This paper presented how to establish a clinically relevant specification (CRS) using in silico physiologically based pharmacokinetic (PBPK) modeling. Three different formulations of model drug products were used in the clinical studies in order to distinguish between bioequivalent (BE) batches from non-BE batches. A human PBPK model was constructed by integrating the clinical and non-clinical observations by using GastroPlusTM software. The developed model was verified by the comparison between human PK behavior observed in clinical studies and human PK behavior predicted from the software. The simulation results were obtained by using the dissolution profiles showing clinically relevant discriminatory power as input variables for the developed PBPK model. For three investigated formulations, the simulated PK behavior was comparable to the PK behavior observed in clinical studies. In addition, in silico BE simulation studies confirmed that the verified PBPK model can successfully reproduce the clinical study results. In conclusion, a CRS was established with the BE simulation by using the verified PBPK model, in order to detect and reject non-BE batches of drug products. The establishment of the CRS is useful for a quality control and finding optimal formulation to accomplish target PK behavior, safety, and efficacy. [ABSTRACT FROM AUTHOR]

Abstract: A simple and sensitive high-performance liquid chromatography (HPLC) method utilizing UV detection was developed for the determination of plasma pyrrole (Py)–imidazole (Im) polyamides in rats and applied to the pharmacokinetic study of compounds. After deproteinization of plasma with methanol, Py–Im polyamides were analyzed with a reversed-phase TSK-GEL ODS-80TM (4.6mm×15.0cm TOSOH Co., Japan) column maintained at 40°C. The mobile phase solvent A was 0.1% acetic acid and the solvent B was HPLC-grade acetonitrile (0–10min, A: 100–20%, B: 0–80% linear gradient; 10–15min, A: 40%, B: 60%). The flow rate was 1.0ml/min. The detection wavelength was set at 310nm. The method was used to determine the plasma concentration time profiles of Py–Im polyamides after intravenous injection. [Copyright &y& Elsevier]

Figure Scheme of the human PBPK model with the ACAT model for edoxaban. [Display omitted] The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 – 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively. [ABSTRACT FROM AUTHOR]