Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review.

Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V2/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V2/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V2/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

Combined impact of hypoalbuminemia and pharmacogenomic variants on voriconazole trough concentration: data from a real-life clinical setting in the Chinese population.

Voriconazole (VRC) displays highly variable pharmacokinetics impacting treatment efficacy and safety. To provide evidence for optimizing VRC therapy regimens, the authors set out to determine the factors impacting VRC steady-state trough concentration (Cmin) in patients with various albumin (Alb) level. A total of 275 blood samples of 120 patients and their clinical characteristics and genotypes of CYP2C19, CYP3A4, CYP3A5, CYP2C9, FMO3, ABCB1, POR, NR1I2 and NR1I3 were included in this study. Results of multivariate linear regression analysis demonstrated that C-reactive protein (CRP) and total bilirubin (T-Bil) were predictors of the VRC Cmin adjusted for dose in patients with hypoalbuminemia (Alb < 35 g/L) (R2 = 0.16, P < 0.001). Additionally, in patients with normal albumin level (Alb ≥ 35 g/L), it resulted in a significant model containing factors of the poor metabolizer (PM) CYP2C19 genotype and CRP level (R2 = 0.26, P < 0.001). Therefore, CRP and T-Bil levels ought to receive greater consideration than genetic factors in patients with hypoalbuminemia.

Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization.

AIMS: The aim of this study was to explore the influence and possible mechanisms of pharmacokinetics-related gene polymorphisms, especially CYP2C19 polymorphisms, and non-genetic factors combined with the inflammatory status on the voriconazole (VRC) metabolism of the Chinese population. METHODS: Clinical studies were performed by collecting more than one VRC trough concentration and C-reactive protein (CRP) level. A total of 265 blood samples were collected from 120 patients. RESULTS: Results of multiple regression analyses demonstrated that CYP2C19 genotypes and albumin (Alb) level remained predictors of Cmin ss/D in patients with no to mild inflammation (R2 = 0.12, P < .001). In addition, in patients with moderate to severe inflammation, it resulted in a significant model containing factors of CRP and total bilirubin (T-Bil) levels (R2 = 0.19, P < .001). In non-clinical studies, 32 rats were divided into control and inflammatory groups, and it was found that the mean residence time (MRT(0-t) ) of VRC in the inflammatory group was significantly longer than that in the control group (P < .001), which may be due to down-regulation of mRNA and protein expression of CYP2C19 (CYP2C6 in rats) through interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3 pathway. CONCLUSIONS: Therefore, the effect of CYP2C19 polymorphisms on VRC metabolism may be masked by inflammatory status, which should be of more concern than CYP2C19 polymorphisms in patients with moderate to severe inflammation. Additionally, the impact of Alb and T-Bil on VRC metabolism should not be disregarded.

An ultrasmall organic synapse for neuromorphic computing.

High-performance organic neuromorphic devices with miniaturized device size and computing capability are essential elements for developing brain-inspired humanoid intelligence technique. However, due to the structural inhomogeneity of most organic materials, downscaling of such devices to nanoscale and their high-density integration into compact matrices with reliable device performance remain challenging at the moment. Herein, based on the design of a semicrystalline polymer PBFCL10 with ordered structure to regulate dense and uniform formation of conductive nanofilaments, we realize an organic synapse with the smallest device dimension of 50 nm and highest integration size of 1 Kb reported thus far. The as-fabricated PBFCL10 synapses can switch between 32 conductance states linearly with a high cycle-to-cycle uniformity of 98.89% and device-to-device uniformity of 99.71%, which are the best results of organic devices. A mixed-signal neuromorphic hardware system based on the organic neuromatrix and FPGA controller is implemented to execute spiking-plasticity-related algorithm for decision-making tasks.

Population Pharmacokinetics and Pharmacogenetics Analyses of Dasatinib in Chinese Patients with Chronic Myeloid Leukemia.

AIMS: Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration. METHODS: PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. RESULTS: The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients. CONCLUSIONS: This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.

Population pharmacokinetics and pharmacogenetics analyses of imatinib in Chinese patients with chronic myeloid leukemia in a real-world situation.

BACKGROUND: Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support individualized medicine. This work aims to characterize population pharmacokinetics in Chinese patients with chronic myeloid leukemia, investigate the effects of several covariates on imatinib exposure, and provide support for personalized medicine and dose reduction. METHODS: A total of 230 patients with chronic myeloid leukemia were enrolled, and 424 steady-state concentration measurements were taken to perform the population pharmacokinetic analysis and Monte Carlo simulations with Phoenix NLME software. The effects of the demographic, biological, and pharmacogenetic (ten SNP corresponding to CYP3A4, CYP3A5, ABCB1, ABCG2, SCL22A1 and POR) covariates on clearance were evaluated. RESULTS: A one-compartmental model best-described imatinib pharmacokinetics. The hemoglobin and the estimated glomerular filtration rate (< 85 mL⋅min-1⋅1.73 m2) were associated with imatinib clearance. The genetic polymorphisms related to pharmacokinetics were not found to have a significant effect on the clearance of imatinib. The final model estimates of parameters are: ka (h-1) = 0.329; Vd/F (L) = 270; CL/F (L⋅h-1) = 7.60. CONCLUSIONS: Key covariates in the study population accounting for variability in imatinib exposure are hemoglobin and the estimated glomerular filtration rate. There is some need for caution when treating patients with moderate-to-severe renal impairment and significant hemoglobin changes.

Impact of individual factors on DNA methylation of drug metabolism genes: A systematic review.

Individual differences in drug response have always existed in clinical treatment. Many non-genetic factors show non-negligible impacts on personalized medicine. Emerging studies have demonstrated epigenetic could connect non-genetic factors and individual treatment differences. We used systematic retrieval methods and reviewed studies that showed individual factors' impact on DNA methylation of drug metabolism genes. In total, 68 studies were included, and half (n = 36) were cohort studies. Six aspects of individual factors were summarized from the perspective of personalized medicine: parental exposure, environmental pollutants exposure, obesity and diet, drugs, gender and others. The most research (n = 11) focused on ABCG1 methylation. The majority of studies showed non-genetic factors could result in a significant DNA methylation alteration in drug metabolism genes, which subsequently affects the pharmacokinetic processes. However, the underlying mechanism remained unknown. Finally, some viewpoints were presented for future research.

Pharmacogenetic Aspects of Drug Metabolizing Enzymes and Transporters in Pediatric Medicine: Study Progress, Clinical Practice and Future Perspectives.

As the activity of certain drug metabolizing enzymes or transporter proteins can vary with age, the effect of ontogenetic and genetic variation on the activity of these enzymes is critical for the accurate prediction of treatment outcomes and toxicity in children. This makes pharmacogenetic research in pediatrics particularly important and urgently needed, but also challenging. This review summarizes pharmacogenetic studies on the effects of genetic polymorphisms on pharmacokinetic parameters and clinical outcomes in pediatric populations for certain drugs, which are commonly prescribed by clinicians across multiple therapeutic areas in a general hospital, organized from those with the most to the least pediatric evidence among each drug category. We also further discuss the research status of the gene-guided dosing regimens and clinical implementation of pediatric pharmacogenetics. More and more drug-gene interactions are demonstrated to have clinical validity for children, and pharmacogenomics in pediatrics have shown evidence-based benefits to enhance the efficacy and precision of existing drug dosing regimens in several therapeutic areas. However, the most important limitation to the implementation is the lack of high-quality, rigorous pediatric prospective clinical studies, so adequately powered interventional clinical trials that support incorporation of pharmacogenetics into the care of children are still needed.

Biomimetic Gradient Hydrogels with High Toughness and Antibacterial Properties.

Traditional hydrogels, as wound dressings, usually exhibit poor mechanical strength and slow drug release performance in clinical biomedical applications. Although various strategies have been investigated to address the above issues, it remains a challenge to develop a simple method for preparing hydrogels with both toughness and controlled drug release performance. In this study, a tannic acid-reinforced poly (sulfobetaine methacrylate) (TAPS) hydrogel was fabricated via free radical polymerization, and the TAPS hydrogel was subjected to a simple electrophoresis process to obtain the hydrogels with a gradient distribution of copper ions. These gradient hydrogels showed tunable mechanical properties by changing the electrophoresis time. When the electrophoresis time reached 15 min, the hydrogel had a tensile strength of 368.14 kPa, a tensile modulus of 16.17 kPa, and a compressive strength of 42.77 MPa. It could be loaded at 50% compressive strain and then unloaded for up to 70 cycles and maintained a constant compressive stress of 1.50 MPa. The controlled release of copper from different sides of the gradient hydrogels was observed. After 6 h of incubation, the hydrogel exhibited a strong bactericidal effect on Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, with low toxicity to NIH/3T3 fibroblasts. The high toughness, controlled release of copper, and enhanced antimicrobial properties of the gradient hydrogels make them excellent candidates for wound dressings in biomedical applications.

Tannic acid-reinforced zwitterionic hydrogels with multi-functionalities for diabetic wound treatment.

Diabetic wounds remain one of the most prevalent hard-to-heal wounds in the clinic. The causative factors impeding the wound healing process include not only the elevated oxidative stress and bacterial infections but also the high and repetitive plantar stress (including compressive pressure and shear stress). Conventional hydrogel dressings are mechanically weak and fragile, limiting their applications in the high stress-loading conditions of diabetic foot ulcers. As such, mechanically tough hydrogel dressings with appropriate bioactivities are highly desirable for diabetic wound treatment. In this study, a mechanically reinforced hydrogel with multiple biofunctionalities was developed via a facile and straightforward strategy of incorporation of tannic acid (TA) in zwitterionic poly(sulfobetaine methacrylate) (polySBMA) hydrogel. The polySBMA hydrogel reinforced by TA showed excellent mechanical property, with the tensile stress and compressive stress up to 93.7 kPa and 18.4 MPa, respectively, and it could resist cyclic compressive stress at ∼200 kPa (maximum in-shoe plantar pressure) for up to 3500 cycles. The TA-reinforced zwitterionic hydrogel exhibited strong adhesion to skin tissue (20.2 kPa), which was expected to reduce the shear stress on the foot. The plantar pressure on the foot was significantly reduced by the application of the resilient hydrogel. Attributed to the antioxidant and antibacterial properties of TA, the hydrogel showed rapid radical scavenging capability and strong bactericidal efficacy against Gram-positive and Gram-negative bacteria. In vitro and in vivo studies confirmed that the hydrogel has good cytocompatibility and negligible skin irritation, and promoted healing of diabetic wounds in mice. Such tough and effective hydrogel with a straightforward preparation strategy holds great promise as wound dressings for diabetic wound treatment.

Internet Access and Nutritional Intake: Evidence from Rural China.

Over the past 4 decades, China has experienced a nutritional transition and has developed the largest population of internet users. In this study, we evaluated the impacts of internet access on the nutritional intake in Chinese rural residents. An IV-Probit-based propensity score matching method was used to determine the impact of internet access on nutritional intake. The data were collected from 10,042 rural households in six Chinese provinces. The results reveal that rural residents with internet access have significantly higher energy, protein, and fat intake than those without. Chinese rural residents with internet access consumed 1.35% (28.62 kcal), 5.02% (2.61 g), and 4.33% (3.30 g) more energy, protein, and fat, respectively. There was heterogeneity in regard to the intake of energy, protein, and fat among those in different income groups. Moreover, non-staple food consumption is the main channel through which internet access affects nutritional intake. The results demonstrate that the local population uses the internet to improve their nutritional status. Further studies are required to investigate the impact of internet use on food consumed away from home and micronutrient intake.

Effects of regenerated cellulose fiber on the characteristics of myofibrillar protein gels.

The study investigated the role of regenerated cellulose (RC) fiber (0, 5 g, 10 g, 15 g and 20 g/100 g) on water holding capacity (WHC), texture, dynamic rheological, secondary structures and microstructure of myofibrillar protein (MP) gels. It was found that the gel WHC and texture properties were enhanced with increased RC fiber. The rheological results indicated that RC fiber did not destroy the normal cross-link of MP, but enhanced the viscoelasticity. The microstructure images proved that RC fiber was filled in the gel network leading to uniform and compact gel structure. Moreover, the pores of water channels became smaller or disappear. The Raman spectroscopy results exhibited that RC fiber facilitated the unfolding of α-helices and promoted the ß-sheet of MP during heating leading to a compact and aggregated network. Consequently, the RC fiber is effective in improving the MP gel functional quality.