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Dengue viruses enter dermal macrophages which are derived from other tissues after mosquito bites. We examined chemotactic factors derived from the dengue vector mosquito, Aedes albopictus, toward a RAW264 murine macrophage cell line. We found that Elizabethkingia anophelis that was isolated from mosquitoes exhibited migration-inducing activity toward RAW264 cells. The active substances were extracted using ethyl acetate to induce chemotactic movements. Chemotactic activity was eluted in the several fractions using the reversed-phase chromatography, suggesting that multiple substances were responsible for the activity. We isolated three bacterial colonies from the wild A. albopictus mosquitoes collected in Toyama Park, Tokyo prefecture, Japan. The bacterial 16S rRNA gene sequences were the most similar to those of Lonsdalea quercina. These bacteria also exhibited migration-inducing activity toward RAW264 cells. The migration-inducing activity of mosquito bacteria might be a new aspect of mosquito-mediated viral infections.

Physiologically-based pharmacokinetic (PBPK) modeling offers a viable approach to predict induction drug-drug interactions (DDIs) with the potential to streamline or reduce clinical trial burden if predictions can be made with sufficient confidence. In the current work, the ability to predict the effect of rifampin, a well-characterized strong CYP3A4 inducer, on 20 CYP3A probes with publicly available PBPK models (often developed using a workflow with optimization following a strong inhibitor DDI study to gain confidence in fraction metabolized by CYP3A4, f m,CYP3A4 , and fraction available after intestinal metabolism, Fg), was assessed. Substrates with a range of f m,CYP3A4 (0.086-1.0), Fg (0.11-1.0) and hepatic availability (0.09-0.96) were included. Predictions were most often accurate for compounds that are not P-gp substrates or that are P-gp substrates but that have high permeability. Case studies for three challenging DDI predictions (i.e., for eliglustat, tofacitinib, and ribociclib) are presented. Along with parameter sensitivity analysis to understand key parameters impacting DDI simulations, alternative model structures should be considered, for example, a mechanistic absorption model instead of a first-order absorption model might be more appropriate for a P-gp substrate with low permeability. Any mechanisms pertinent to the CYP3A substrate that rifampin might impact (e.g., induction of other enzymes or P-gp) should be considered for inclusion in the model. PBPK modeling was shown to be an effective tool to predict induction DDIs with rifampin for CYP3A substrates with limited mechanistic complications, increasing confidence in the rifampin model. While this analysis focused on rifampin, the learnings may apply to other inducers., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady-state systemic exposure on co-administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5-12.5 mg/kg and fluconazole at 3-12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co-administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0-t) was increased by approximately sevenfold and five to threefold by strong and high-moderate and low-moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

In recent years, a wide variety of materials have been used in dental implant treatment. In selecting the superstructures and abutments to be used it is important to consider their potential effect on the stability and durability of the planned implant. Excessive force applied to an implant during maintenance commonly results in complications, such as fracture of the superstructure or abutment, and loosening or fracture of the screws. This report describes a case of implant treatment for a 23-year-old man with esthetic disturbance due to trauma to the maxillary anterior teeth. The left maxillary central incisor could not be conserved due to this trauma, which had been caused by a traffic accident. After extraction, the tooth was restored with an anterior bridge. The crown of the left maxillary lateral incisor was fractured at the crown margin and, at the patient's request, implant treatment was selected as the restorative treatment for the missing tooth. A thorough preoperative examination was performed using placement simulation software. One titanium screw-type implant was placed in the maxillary left central incisor under local anesthesia. An all-ceramic crown with a zirconia frame was placed as a screw-fixed direct superstructure. At one year postoperatively, however, the superstructure and abutment became detached due to trauma. The fractured zirconia abutment was removed and replaced with a remanufactured abutment and superstructure. The patient has reported no subsequent dental complaint over the last 11 years. In this case, a surface analysis of the fractured zirconia abutment was performed. The scanned images revealed a difference in the fracture surfaces between the tensile and compressive sides, and electron probe microanalysis demonstrated the presence of titanium on the fracture surface. It was inferred that the hard zirconia abutment had scraped the titanium from the internal surface of the implant.

Aim: In March 2021, the Japanese Ministry of Health, Labour and Welfare revised the optimal gestational weight gain standards. In this study, we examined whether this revision affected gestational weight gain and low birth weight rates., Methods: We analyzed the records of singleton pregnant women who underwent checkups from their 1st trimester and delivered at our institute after 37 weeks between 2020 and 2021 (before the revision) and between 2022 and 2023 (after the revision). Pregnancy outcomes were assessed in the following four groups stratified by pre-pregnancy body mass index (BMI): underweight (BMI: <18.5 kg/m 2 ), normal-weight (BMI: 18.5-24.9 kg/m 2 ), overweight (BMI: 25-29.9 kg/m 2 ), and obese (BMI: ≥30 kg/m 2 ). Leaflets on the optimal gestational weight gain standards for each group were distributed to all pregnant women at the first prenatal checkup., Results: In each group, gestational weight gain did not change before and after the revision, with the corresponding values of 10.8 kg and 11.1 kg in the underweight (p = 0.94), 10.7 kg and 10.4 kg in the normal weight (p = 0.14), 9.7 kg and 9.2 kg in the overweight (p = 0.32), and 7.4 kg and 6.7 kg in the obese (p = 0.44) groups. Furthermore, the prevalence of low birth weight did not decrease in all groups., Conclusions: No significant differences in gestational weight gain or low birth weight were observed after the revision of the 2021 gestational weight gain recommendations. Merely distributing leaflets to pregnant women may not be sufficient to improve gestational weight gain or reduce low birth weight rates., (© 2024 Japan Society of Obstetrics and Gynecology.)

Background: Maximum phonation time (MPT) is used to assess speech and other oral rehabilitation-related issues. Various factors contribute to MPT decline in older individuals. Although the impact of physical frailty on MPT has been suggested, this has not been conclusively determined., Objective: To examine the relationship between MPT and physical frailty in community-dwelling individuals aged ≥60 years who were independently mobile. MPT-associated factors were investigated., Methods: This cross-sectional study analysed the clinical data of 122 patients (age [interquartile range]: 80.0 [74.0-83.0] years) without dementia who visited a neurology department between 1 February 2021 and 31 January 2023. Investigated factors included age, sex, weight, height, body mass index, smoking history, grip strength, functional independence measure, vital capacity, oral diadochokinesis, MPT and the Japanese Cardiovascular Health Study score. Physical frailty was assessed based on the total score from five items (weight loss, weakness, exhaustion, slowness and low physical activity). The relationship between MPT and physical frailty was examined using Spearman's rank correlation coefficient and hierarchical multiple regression analysis., Results: The MPT was negatively correlated with age (r = -0.347, p < .01) and physical frailty (r = -0.681, p < .01) and positively correlated with vital capacity (r = 0.474, p < .01) and height (r = 0.248, p < .01). The hierarchical multiple regression analysis, conducted with MPT as the dependent variable, demonstrated that physical frailty (β = -.59, 95% confidence interval: -0.74 to 0.43, p < .001) had a strong influence on MPT., Conclusion: In older individuals, MPT is associated with physical frailty. When assessing MPT in clinical settings, it is advisable to perform a concurrent assessment of physical frailty., (© 2024 John Wiley & Sons Ltd.)

Hepatic impairment, due to liver cirrhosis, decreases the activity of cytochrome P450 enzymes (CYPs). The use of physiologically based pharmacokinetic (PBPK) modeling to predict this effect for CYP substrates has been well-established, but the effect of cirrhosis on uridine-glucuronosyltransferase (UGT) activities is less studied and few PBPK models have been reported. UGT enzymes are involved in primary N -glucuronidation of midazolam and glucuronidation of 1'-OH-midazolam following CYP3A hydroxylation. In this study, Simcyp was used to establish PBPK models for midazolam, its primary metabolites midazolam- N -glucuronide (UGT1A4) and 1'-OH midazolam (CYP3A4/3A5), and the secondary metabolite 1'-OH-midazolam- O -glucuronide (UGT2B7/2B4), allowing to simulate the impact of liver cirrhosis on the primary and secondary glucuronidation of midazolam. The model was verified in noncirrhotic subjects before extrapolation to cirrhotic patients of Child-Pugh (CP) classes A, B, and C. Our model successfully predicted the exposures of midazolam and its metabolites in noncirrhotic and cirrhotic patients, with 86% of observed plasma concentrations within 5th-95th percentiles of predictions and observed geometrical mean of area under the plasma concentration curve between 0 hours to infinity and maximal plasma concentration within 0.7- to 1.43-fold of predictions. The simulated metabolic ratio defined as the ratio of the glucuronide metabolite AUC over the parent compound AUC (AUC glucuronide /AUC parent , metabolic ratio [MR]), was calculated for midazolam- N -glucuronide to midazolam (indicative of UGT1A4 activity) and decreased by 40% (CP A), 48% (CP B), and 75% (CP C). For 1'-OH-midazolam- O -glucuronide to 1'-OH-midazolam, the MR (indicative of UGT2B7/2B4 activity) dropped by 35% (CP A), 51% (CP B), and 64% (CP C). These predicted MRs were corroborated by the observed data. This work thus increases confidence in Simcyp predictions of the effect of liver cirrhosis on the pharmacokinetics of UGT1A4 and UGT2B7/UGT2B4 substrates. SIGNIFICANCE STATEMENT: This article presents a physiologically based pharmacokinetic model for midazolam and its metabolites and verifies the accurate simulation of pharmacokinetic profiles when using the Simcyp hepatic impairment population models. Exposure changes of midazolam- N -glucuronide and 1'-OH-midazolam- O -glucuronide reflect the impact of decreases in UGT1A4 and UGT2B7/2B4 glucuronidation activity in cirrhotic patients. The approach used in this study may be extended to verify the modeling of other uridine glucuronosyltransferase enzymes affected by liver cirrhosis., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Prevention of postoperative nausea and vomiting (PONV) is important to achieve DREAM (drinking, eating, mobilization). Ondansetron inhibits PONV, but its effects on postoperative food intake have not been investigated. This study aimed to examine associations between ondansetron and PONV incidence, and postoperative food intake., Methods: This retrospective study included adult patients (n = 632) who underwent laparoscopic gynecological surgery at Kyushu University Hospital between January 2017 and June 2023. Outcomes were PONV on the day of surgery, PONV up to the day after surgery, and food intake, which was assessed for breakfast and lunch on the day after surgery. Odds ratios (ORs) for PONV incidence and postoperative no-food intake were calculated between those with and without ondansetron during surgery. Multivariable-adjusted analysis was performed using possible confounding factors for PONV. Synergistic effects of combining ondansetron with dexamethasone or total intravenous anesthesia (TIVA) were assessed., Results: Multivariable-adjusted ORs for PONV on the day of surgery and up to the day after surgery were 0.56 (95% confidence interval, 0.32-0.99, p = 0.04) and 0.52 (0.30-0.93, p = 0.03), respectively, in the ondansetron group (n = 84) compared with the non-ondansetron group (n = 548). In contrast, multivariable-adjusted ORs for no-food intake of breakfast and lunch the day after surgery in the ondansetron group compared with the non-ondansetron group were not significant. Analysis of synergistic effects on PONV showed no significant interaction between ondansetron and dexamethasone or ondansetron and TIVA combinations., Conclusion: Ondansetron administration during surgery was significantly associated with decreased PONV risk but was not associated with food intake the day after surgery., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Osteoporosis is characterized by bone loss and deterioration in bone microstructure, leading to bone fragility. It is strongly correlated with menopause in women. Previously, we reported that diets supplemented with a kudzu (Pueraria lobata) vine extract suppressed bone resorption in ovariectomized (OVX) mice, a postmenopausal model. The main isoflavone in kudzu is puerarin (daidzein-8-C-glycoside). Puerarin (daidzein-8-C-glycoside), which is main isoflavone of kudzu, probably contributes to the beneficial effect. However, the underlying mechanism is unclear. Therefore, the nutrikinetics of puerarin and the comparison with the suppressive effects of kudzu isoflavones on osteoclast differentiation was examined in this study. We demonstrated that orally administered puerarin was absorbed from the gut and entered the circulation in an intact form. In addition, puerarin accumulated in RAW264.7 pre-osteoclast cells in a time-dependent manner. Tartrate-resistant acid phosphatase activity was decreased by puerarin treatment in a concentration-dependent manner in RAW264.7 cells stimulated with the receptor activator of nuclear factor kappa-B ligand. Ovariectomy-induced elevated bone resorption was suppressed, and the fragile bone strength was improved by puerarin ingestion in the diet. These findings suggested that orally administered puerarin was localized in bone tissue and suppressed bone resorption and osteoclastogenesis in ovariectomized mice.

This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr, little cytotoxicity was observed, although reduced glutathione (GSH) content decreased in a concentration-dependent manner. Significant cytotoxicity and reactive oxygen species (ROS) production were observed when intracellular GSH content was reduced by treatment with L-buthionine-(S, R)-sulphoximine. The involvement of myeloperoxidase (MPO) metabolism was suggested, as when HL-60 cells were exposed to a reaction mixture of vesnarinone-MPO/H 2 O 2 /Cl - , cytotoxicity was also observed. In contrast, the presence of GSH (1 mM) protected against these cytotoxic effects. Liquid chromatography-mass spectrometry analysis of the MPO/H 2 O 2 /Cl - reaction mixture revealed that vesnarinone was converted into two metabolites, (4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 1: M1] and 1-chloro-4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 2: M2]). M2 was identified as the N-chloramine form, a reactive metabolite of M1. Interestingly, M2 was converted to M1, which was accompanied by the conversion of GSH to oxidized GSH (GSSG). Furthermore, when HL-60 cells were exposed to synthetic M1 and M2 for 24 hr, M2 caused dose-dependent cytotoxicity, whereas M1 did not. Cells were protected from M2-derived cytotoxicity by the presence of GSH. In conclusion, we present the first demonstration of the cytotoxic effects and ROS production resulting from the MPO/H 2 O 2 /Cl - metabolic reaction of vesnarinone and newly identified the causative metabolite, M2, as the N-chloramine metabolite of M1, which induces cytotoxicity in HL-60 cells. Moreover, a protective role of GSH against the cytotoxicity was revealed. These findings suggest a possible nonimmunological cause of vesnarinone agranulocytosis.

Background/aim: Eribulin is an effective chemotherapeutic agent for advanced and metastatic breast cancer. However, severe neutropenia occurs in 30-40% of patients and interferes with the recommended treatment schedule. Neutropenia is a major cause of treatment interruptions, delays, or even relative dose reductions. This study aimed to examine the risk factors for severe neutropenia after eribulin treatment., Patients and Methods: We retrospectively evaluated 263 patients with metastatic breast cancer who had received eribulin therapy. Risk factors for severe neutropenia in the first cycle were evaluated., Results: Severe neutropenia in cycle 1 occurred in 50% of the patients. Multivariate analysis suggested six risk factors for severe neutropenia: low baseline neutrophil count and body mass index, high aspartate aminotransferase and bilirubin levels, creatinine clearance (CrCl) less than 50 ml/min, and eribulin dose of 1.4 mg/m 2 Conclusion: This is one of the few studies to simultaneously examine both hepatic and renal functions in relation to severe neutropenia induced by eribulin. We have provided important information to support the close monitoring of patients with these risk factors and subsequent dosage adjustments, if necessary., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The purpose of this survey was to examine the status of radiotherapy in Japan based on the cases registered in the Japanese Radiation Oncology Database (JROD), from 2015 to 2021, and to provide basic data to help improve the usefulness of the JROD in the future. The study population consisted of patients who underwent radiotherapy between 2014 and 2020 and did not opt out of the study. The survey item data analyzed in this study were entered into the database at each radiotherapy institution by referring to medical records from the preceding year. Our results show that the number of registered radiotherapy institutions and cases increased by ~50% in 2019 compared to those in 2015 (to 113 institutions and 60 575 cases, respectively). Among the survey item categories, the registration rate was lowest for prognostic information (13.9% on average over the 7-year period). In terms of the Japanese Society for Radiation Oncology disease site, the breast; lung, trachea and mediastinum and urogenital sites accounted for >50% of the total cases. The average survival and mortality rates over the 7-year study period were 67.4 and 17.4%, respectively. The X-ray radiotherapy completion rate exceeded 90% for all years and across all disease categories. 192Ir-based brachytherapy and 223Ra-based radionuclide therapy accounted for an average of 61.9 and 44.6%, respectively, of all corresponding cases over the 7-year period. In conclusion, this survey enables us to infer the actual status of radiotherapy in Japan based on the analysis of relevant nationwide data., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Rationale and Objectives: Coronary inflammation related to high-risk hemorrhagic plaques can be captured by the perivascular fat attenuation index (FAI) using coronary computed tomography angiography (CCTA). Since the FAI is susceptible to image noise, we believe deep learning (DL)-based post hoc noise reduction can improve diagnostic capability. We aimed to assess the diagnostic performance of the FAI in DL-based denoised high-fidelity CCTA images compared with coronary plaque magnetic resonance imaging (MRI) delivered high-intensity hemorrhagic plaques (HIPs)., Materials and Methods: We retrospectively reviewed 43 patients who underwent CCTA and coronary plaque MRI. We generated high-fidelity CCTA images by denoising the standard CCTA images using a residual dense network that supervised the denoising task by averaging three cardiac phases with nonrigid registration. We measured the FAIs as the mean CT value of all voxels (range of -190 to -30 HU) located within a radial distance from the outer proximal right coronary artery wall. The diagnostic reference standard was defined as HIPs (high-risk hemorrhagic plaques) using MRI. The diagnostic performance of the FAI in the original and denoised images was assessed using receiver operating characteristic curves., Results: Of 43 patients, 13 had HIPs. The denoised CCTA improved the area under the curve (0.89 [95% confidence interval (CI) 0.78-0.99]) of the FAI compared with that in the original image (0.77 [95% CI, 0.62-0.91], p = 0.008). The optimal cutoff value for predicting HIPs in denoised CCTA was -69 HU with 0.85 (11/13) sensitivity, 0.79 (25/30) specificity, and 0.80 (36/43) accuracy., Conclusion: DL-based denoised high-fidelity CCTA improved the AUC and specificity of the FAI for predicting HIPs., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Physiologically-based pharmacokinetic (PBPK) modeling has become the established method for predicting human pharmacokinetics (PK) and drug-drug interactions (DDI). The number of drugs cleared by non-CYP enzyme metabolism has increased steadily and to date, there is no consolidated overview of PBPK modeling for drugs cleared by non-CYP enzymes. This review aims to describe the state-of-the-art for PBPK modeling for drugs cleared via non-CYP enzymes, to identify successful strategies, to describe gaps and to provide suggestion to overcome them. To this end, we conducted a detailed literature search and found 58 articles published before the 1 st of January 2023 containing 95 examples of clinical PBPK models for 62 non-CYP enzyme substrates. Reviewed articles covered the drug clearance by uridine 5'-diphospho-glucuronosyltransferases (UGTs), aldehyde oxidase (AO), flavin-containing monooxygenases (FMOs), sulfotransferases (SULTs) and carboxylesterases (CES), with UGT2B7, UGT1A9, CES1, FMO3 and AO being the enzymes most frequently involved. In vitro-in vivo extrapolation (IVIVE) of intrinsic clearance and the bottom-up PBPK modeling involving non-CYP enzymes remains challenging. We observed that the middle-out modeling approach was applied in 80% of the cases, with metabolism parameters optimized in 73% of the models. Our review could not identify a standardized approach used for model optimization based on clinical data, with manual optimization employed most frequently. Successful development of models for UGT2B7, UGT1A9, CES1, and FMO3 substrates provides a foundation for other drugs metabolized by these enzymes and guides the way forward in creating PBPK models for other enzymes in these families. Significance Statement Our review charts the rise of PBPK modeling for drugs cleared by non-CYP enzymes. Analyzing 58 articles and 62 non-CYP enzyme substrates, we found that UGTs, AO, FMOs, SULTs, and CES were the main enzyme families involved and that UGT2B7, UGT1A9, CES1, FMO3 and AO are the individual enzymes with the strongest PBPK modeling precedents. Approaches established for these enzymes can now be extended to additional substrates and to drugs metabolized by enzymes that are similarly well characterized., (Copyright © 2023 American Society for Pharmacology and Experimental Therapeutics.)

Aims: RO7049389 (linvencorvir) is a developmental oral treatment for chronic hepatitis B virus infection. The aim of this work was to conduct mass balance (MB) and absolute bioavailability (BA) analyses in healthy volunteers, alongside in vitro evaluations of the metabolism of RO7049389 and a major circulating active metabolite M5 in human hepatocytes, and physiologically based pharmacokinetic (PBPK) modelling to refine the underlying drug disposition paradigm., Methods: Participants in the clinical study (MB: Caucasian, male, n = 6; BA: Caucasian and Asian, male and female, n = 16, 8 in each ethnic groups) received oral [ 14 C] or unlabelled RO7049389 (600/1000 mg) followed by 100 μg intravenous [ 13 C]RO7049389. Metabolic pathways with fractions metabolized-obtained from the in vitro incubation results of 10 μM [ 14 C]RO7049389 and 1 μM M5 with (long-term cocultured) human hepatocytes in the absence and presence of the cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole-were used to complement the PBPK models, alongside the clinical MB and BA data., Results: The model performance in predicting the pharmacokinetic profiles of RO7049389 and M5 aligned with clinical observations in Caucasians and was also successfully applied to Asians. Accordingly, the drug disposition pathways for RO7049389 were postulated with newly characterized estimates of the fractions: biliary excretion by P-glycoprotein (~41%), direct glucuronidation via uridine 5'-diphosphoglucuronosyltransferase 1A3 (~11%), hexose conjugation (~6%), oxidation by CYP3A4 (~28%) and other oxidation reactions (~9%)., Conclusion: These results support the ongoing clinical development program for RO7049389 and highlight the broader value of PBPK and MB analyses in drug development., (© 2023 British Pharmacological Society.)

Background/aim: Alectinib is recommended for anaplastic lymphoma kinase fusion gene-positive non-small cell lung cancer. We have experienced early alectinib discontinuation due to disease progression and adverse effects in real world. Because alectinib has a high protein-binding rate of >99%, low serum albumin may increase the concentration of free drug and affect efficacy and adverse events. However, no association between serum albumin and the clinical impact of alectinib has been reported. The purpose of this study was to determine the effect of serum albumin on time-to-treatment failure (TTF) in alectinib., Patients and Methods: Fifty-six patients who were admitted to four hospitals (National Hospital Organization Hokkaido Cancer Center, Sapporo Minami-Sanjo Hospital, KKR Sapporo Medical Center, Otaru General Hospital) between October 2014 and September 2020 were retrospectively evaluated to identify those treated with alectinib., Results: The multivariate analysis showed that the risk of discontinuation was significantly higher with serum albumin <3.6 g/dl compared to ≥3.6 g/dl at the start of alectinib administration (hazard ratio=3.00; 95% confidence interval=1.36-6.66; p<0.01). On Kaplan-Meier curves, TTF for serum albumin <3.6 was significantly shorter than that for ≥3.6. (median TTF: 12.1 months vs. not reach, p<0.01)., Conclusion: To the best of our knowledge, this study is the first to report that serum albumin <3.6 g/dl at alectinib induction is associated with poor TTF. Low serum albumin is a poor prognostic factor in cancer patients. Thus, serum albumin levels must be measured before treatment., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tacrolimus is a crucial immunosuppressant for organ transplant patients, requiring therapeutic drug monitoring due to its variable exposure after oral intake. Physiologically based pharmacokinetic (PBPK) modelling has provided insights into tacrolimus disposition in adults but has limited application in paediatrics. This study investigated age dependency in tacrolimus exposure at the levels of absorption, metabolism, and distribution. Based on the literature data, a PBPK model was developed to predict tacrolimus exposure in adults after intravenous and oral administration. This model was then extrapolated to the paediatric population, using a unique reference dataset of kidney transplant patients. Selecting adequate ontogeny profiles for hepatic and intestinal CYP3A4 appeared critical to using the model in children. The best model performance was achieved by using the Upreti ontogeny in both the liver and intestines. To mechanistically evaluate the impact of absorption on tacrolimus exposure, biorelevant in vitro solubility and dissolution data were obtained. A relatively fast and complete release of tacrolimus from its amorphous formulation was observed when mimicking adult or paediatric dissolution conditions (dose, fluid volume). In both the adult and paediatric PBPK models, the in vitro dissolution profiles could be adequately substituted by diffusion-layer-based dissolution modelling. At the level of distribution, sensitivity analysis suggested that differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in paediatric patients.

Background and Objective: The impact of liver cirrhosis on the activity of UDP-glucuronosyltransferases (UGTs) is currently not well characterized. We investigated the glucuronidation capacity and glucuronide accumulation in patients with liver cirrhosis., Methods: We administered the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, midazolam) to patients with liver cirrhosis (n = 16 Child A, n = 15 Child B, n = 5 Child C) and n = 12 control subjects and obtained pharmacokinetic profiles of substrates and primary metabolites and their glucuronides., Results: Caffeine and its metabolite paraxanthine were only slightly glucuronidated. The metabolic ratio (AUC glucuronide /AUC parent , MR) was not affected for caffeine but decreased by 60% for paraxanthine glucuronide formation in Child C patients. Efavirenz was not glucuronidated whereas 8-hydroxyefavirenz was efficiently glucuronidated. The MR of 8-hydroxyefavirenz-glucuronide formation increased three-fold in Child C patients and was negatively correlated with the glomerular filtration rate. Flurbiprofen and omeprazole were not glucuronidated. 4-Hydroxyflurbiprofen and 5-hydroxyomeprazole were both glucuronidated but the corresponding MRs for glucuronide formation were not affected by liver cirrhosis. Metoprolol, but not α-hydroxymetoprolol, was glucuronidated, and the MR for metoprolol-glucuronide formation dropped by 60% in Child C patients. Both midazolam and its metabolite 1'-hydroxymidazolam underwent glucuronidation, and the corresponding MRs for glucuronide formation dropped by approximately 80% in Child C patients. No relevant glucuronide accumulation occurred in patients with liver cirrhosis., Conclusions: Detailed analysis revealed that liver cirrhosis may affect the activity of UGTs of the UGT1A and UGT2B subfamilies according to liver function. Clinically significant glucuronide accumulation did not occur in the population investigated., Clinical Trial Registration: NCT03337945., (© 2023. The Author(s).)

Hepatocyte intrinsic clearance (CL int ) and methods of in vitro-in vivo extrapolation (IVIVE) are often used to predict plasma clearance (CL p ) in drug discovery. While the prediction success of this approach is dependent on the chemotype, specific molecular properties and drug design features that govern these outcomes are poorly understood. To address this challenge, we investigated the success of prospective mouse CL p IVIVE across 2142 chemically diverse compounds. Dilution scaling, which assumes that the free fraction in hepatocyte incubations ( f u,inc ) is governed by binding to the 10% of serum in the incubation medium, was used as our default CL p IVIVE approach. Results show that predictions of CL p are better for smaller (molecular weight (MW) < 500 Da), less polar (total polar surface area (TPSA) < 100 Å 2 , hydrogen bond donor (HBD) ≤1, hydrogen bond acceptor (HBA) ≤ 6), lipophilic (log  D > 3), and neutral compounds, with low HBD count playing the key role. If compounds are classified according to their chemical space, predictions were good for compounds resembling central nervous system (CNS) drugs [average absolute fold error (AAFE) of 2.05, average fold error (AFE) of 0.90], moderate for classical druglike compounds (according to Lipinski, Veber, and Ghose guidelines; AAFE of 2.55; AFE of 0.68), and poor for nonclassical "beyond the rule of 5" compounds (AAFE of 3.31; AFE of 0.41). From the perspective of measured druglike properties, predictions of CL p were better for compounds with moderate-to-high hepatocyte CL int (>10 μL/min/10 6 cells), high passive cellular permeability ( P app > 100 nm/s), and moderate observed CL p (5-50 mL/min/kg). Influences of plasma protein binding ( f u,p ) and P-glycoprotein (Pgp) apical efflux ratio (AP-ER) were less pronounced. If the extended clearance classification system (ECCS) is applied, predictions were good for class 2 ( P app > 50 nm/s; neutral or basic; AAFE of 2.35; AFE of 0.70) and acceptable for class 1A compounds (AAFE of 2.98; AFE of 0.70). Classes 1B, 3 A/B, and 4 showed poor outcomes (AAFE > 3.80; AFE < 0.60). Functional groups trending toward weaker CL p IVIVE were esters, carbamates, sulfonamides, carboxylic acids, ketones, primary and secondary amines, primary alcohols, oxetanes, and compounds liable to aldehyde oxidase metabolism, likely due to multifactorial reasons. Multivariate analysis showed that multiple properties are relevant, combining together to define the overall success of CL p IVIVE. Our results indicate that the current practice of prospective CL p IVIVE is suitable only for CNS-like compounds and well-behaved classical druglike space (e.g., high permeability or ECCS class 2) without challenging functional groups. Unfortunately, based on existing mouse data, prospective CL p IVIVE for complex and nonclassical chemotypes is poor and hardly better than random guessing. This is likely due to complexities such as extrahepatic metabolism and transporter-mediated disposition which are poorly captured by this methodology. With small-molecule drug discovery increasingly evolving toward nonclassical and complex chemotypes, existing CL p IVIVE methodology will require improvement. While empirical correction factors may bridge the gap in the near future, improved and new in vitro assays, data integration models, and machine learning (ML) methods are increasingly needed to address this challenge and reduce the number of nonclinical pharmacokinetic (PK) studies.

The feasibility and efficacy of particle beam therapy (PBT) using protons or carbon ions were compared with those of photon-based stereotactic body radiotherapy (SBRT) for primary renal cell carcinoma (RCC) via a systematic review and nationwide registry for PBT (Japanese Society for Radiation Oncology [JASTRO] particle therapy committee). Between July 2016 and May 2019, 20 patients with non-metastatic RCC who were treated at six Japanese institutes (using protons at three, using carbon ions at the other three) were registered in the nationwide database and followed up prospectively. The 20 patients comprised 15 men and had a median age of 67 (range: 57-88) years. The total radiation dose was 66-79.6 Gy (relative biological effectiveness [RBE]). Over a median follow up of 31 months, the 3-year rates of overall survival (OS) and local control (LC) were 100% and 94.4%, respectively. No grade ≥ 3 toxicities were observed. Based on a random effects model, a meta-analysis including the present results revealed 3-year OS rates after SBRT and PBT of 75.3% (95% CI: 57.3-86.6) and 94.3% (95% CI: 86.8-97.6), respectively (P = 0.005), but the difference in LC rates between the two methods was not observed (P = 0.63). PBT is expected to have similar if not better treatment results compared with SBRT for primary renal cancer. In particular, PBT was shown to be effective even for large RCC and could provide a therapeutic option when SBRT is not indicated., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Introduction: The association between abemaciclib dose reduction and treatment adherence is not clear. In this study, we examined real-world data of Japanese patients with advanced breast cancer (ABC) to determine how abemaciclib dose reduction is related to treatment continuation., Methods: This retrospective observational study involved 120 consecutive patients with ABC who received abemaciclib from December 2018 to March 2021. The time to treatment failure (TTF) was estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify factors associated with a TTF of >365 days (TTF365)., Results: According to the dose reduction during treatment, the patients were classified into 100, 200, and 300 mg/day abemaciclib groups. The 300 mg/day group had a TTF of 7.4 months, whereas the 100 and 200 mg/day groups had significantly longer TTFs (17.9 and 17.3 months, respectively; P = 0.0002). In this study, relative to the 300 mg/day arm, TTF was improved in 200mg/day arm and 100 mg/day arm (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.33-0.93) and [HR], 0.37; 95% CI, 0.19-0.74). For patients who received 300mg/day of abemaciclib dose arm, 200mg/day, and 100mg/day, the median TTF was 7.4 ,17.9 and 17.3 months. The frequently reported adverse effects (AEs) were anemia, increased blood creatinine levels, diarrhea, and neutropenia (90%, 83%, 83%, and 75% of the patients, respectively). Neutropenia, fatigue, and diarrhea were the top AEs causing dose reduction. A multivariate analysis that examined factors associated with achieving TTF 365 confirmed that dose down was an important factor (odds ratio: 3.95, 95% confidence interval: 1.68-9.36, P = 0.002)., Conclusions: In this study, the 100 and 200 mg/day groups had a longer TTF than the 300 mg/day group, and dose reduction was identified as an important factor in achieving longer TTF.

Background: The degrees of adverse effects with carboplatin (CBDCA) are influenced by interindividual differences in the area under the curve (AUC), whereas renal function is not considered in the CBDCA dose design for dexamethasone, etoposide, ifosfamide, and CBDCA (DeVIC) therapy. We conducted this study to evaluate the association between the AUC and incidence of severe thrombocytopenia in patients treated with DeVIC with or without rituximab (DeVIC ± R)., Methods: We retrospectively analyzed clinical data for 36 patients with non-Hodgkin's lymphoma who received DeVIC ± R between May 2013 and January 2021 at the National Hospital Organization Hokkaido Cancer Center. The AUC of CBDCA (AUC actual ) was calculated backward using a variant of the Calvert formula., Results: The median AUC actual was 4.6 (interquartile range: 4.3-5.3) min mg/mL and AUC actual was negatively correlated with the nadir platelet count (r = -0.45; P < 0.01). Multivariate analysis showed that AUC actual ≥ 4.3 versus < 4.3 was an independent factor predictive of severe thrombocytopenia (odds ratio: 19.3, and 95% confidence interval: 1.45-258; P = 0.02)., Conclusion: This study suggests that the CBDCA dosing design considering renal function can reduce the risk of severe thrombocytopenia in DeVIC ± R therapy.

Typically, therapeutic proteins (TPs) have a low risk for eliciting meaningful drug interactions (DIs). However, there are select instances where TP drug interactions (TP-DIs) of clinical concern can occur. This white paper discusses the various types of TP-DIs involving mechanisms such as changes in disease state, target-mediated drug disposition, neonatal Fc receptor (FcRn), or antidrug antibodies formation. The nature of TP drug interaction being investigated should determine whether the examination is conducted as a standalone TP-DI study in healthy participants, in patients, or assessed via population pharmacokinetic analysis. DIs involving antibody-drug conjugates are discussed briefly, but the primary focus here will be DIs involving cytokine modulation. Cytokine modulation can occur directly by certain TPs, or indirectly due to moderate to severe inflammation, infection, or injury. Disease states that have been shown to result in indirect disease-DIs that are clinically meaningful have been listed (i.e., typically a twofold change in the systemic exposure of a coadministered sensitive cytochrome P450 substrate drug). Type of disease and severity of inflammation should be the primary drivers for risk assessment for disease-DIs. While more clinical inflammatory marker data needs to be collected, the use of two or more clinical inflammatory markers (such as C-reactive protein, albumin, or interleukin 6) may help broadly categorize whether the predicted magnitude of inflammatory disease-DI risk is negligible, weak, or moderate to strong. Based on current knowledge, clinical DI studies are not necessary for all TPs, and should no longer be conducted in certain disease patient populations such as psoriasis, which do not have sufficient systemic inflammation to cause a meaningful indirect disease-DI., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Failure to perform adequate dose adjustment in patients with liver cirrhosis may be associated with increased toxicity. We compared the prediction of area under the curve (AUC) and clearance for the six compounds of the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, and midazolam) using a well-known physiology-based pharmacokinetic approach (physiologically-based pharmacokinetic [PBPK] approach, Simcyp) and a novel top-down method based on the systemic clearance in healthy volunteers adjusted for markers of liver and renal dysfunction ("top-down approach"). With few exceptions, plasma concentration-time curves were accurately predicted by the PBPK approach. In comparison to the measured AUC and clearance of these drugs in patients with liver cirrhosis and healthy controls, except for efavirenz, the estimates of both approaches were within two standard deviations of the mean for total and free drug concentrations. For both approaches, a correction factor for dose adjustment in patients with liver cirrhosis could be calculated for the drugs administered. AUCs calculated using the adjusted doses were comparable to the AUCs measured in control subjects, with slightly more accurate predictions generated by the PBPK approach. For drugs with a free fraction < 50%, predictions using free drug concentrations were more accurate than with total drug concentrations. In conclusion, both methods provided good qualitative predictions of the changes by liver cirrhosis in the pharmacokinetics of the six compounds investigated. The top-down approach is easier to implement but the PBPK approach predicted changes in drug exposure more accurately than the top-down approach and provided reliable estimates for plasma concentrations., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Drug-drug interaction (DDI) assessments are well defined in health authority guidelines for small molecule drugs, and US Food and Drug Administration (FDA) draft guidance is now available for therapeutic proteins. However, there are currently no regulatory guidelines outlining DDI assessments for therapeutic peptides, which poses significant uncertainty and challenges during drug development for this heterogenous class of molecules. A cross-industry peptide DDI working group consisting of experts from 10 leading companies was formed under the sponsorship of the European Federation of Pharmaceutical Industries and Associations. We aimed to capture the range of DDI studies undertaken for peptide drugs by (i) anonymously surveying relevant companies involved in peptide drug development to better understand DDI study type/timing currently performed and (ii) compiling a database containing in vitro / clinical DDI data from submission packages for recently approved peptide drugs. Our analyses highlight significant gaps and uncertainty in the field. For example, the reported timing of in vitro peptide DDI studies, if performed, vary substantially across responding companies from early research to phase III. Nearly all in vitro cytochrome P450 / transporter inhibition studies reported in the survey were negative. For the few positive hits reported, no clinical follow-up studies were performed, questioning the clinical relevance of these findings. Furthermore, available submission packages reveal DDI likelihood is low for peptides >2 kDa, making it reasonable to adopt a risk-based approach during drug development for larger peptides. By benchmarking the landscape of peptide DDI activities across the industry, we set the stage for future discussions with health authorities on harmonizing peptide DDI approaches., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: To assess low-contrast areas such as plaque and coronary artery stenosis, coronary computed tomography angiography (CCTA) needs to provide images with lower noise without increasing radiation doses., Purpose: To develop a deep learning-based noise-reduction method for CCTA using four-dimensional noise reduction (4DNR) as the ground truth for supervised learning., Material and Methods: \We retrospectively collected 100 retrospective ECG-gated CCTAs. We created 4DNR images using non-rigid registration and weighted averaging three timeline CCTA volumetric data with intervals of 50 ms in the mid-diastolic phase. Our method set the original reconstructed image as the input and the 4DNR as the target image and obtained the noise-reduced image via residual learning. We evaluated the objective image quality of the original and deep learning-based noise-reduction (DLNR) images based on the image noise of the aorta and the contrast-to-noise ratio (CNR) of the coronary arteries. Further, a board-certified radiologist evaluated the blurring of several heart structures using a 5-point Likert scale subjectively and assigned a coronary artery disease reporting and data system (CAD-RADS) category independently., Results: DLNR CCTAs showed 64.5% lower image noise ( P  < 0.001) and achieved a 2.9 times higher CNR of coronary arteries than that in original images, without significant blurring in subjective comparison ( P  > 0.1). The intra-observer agreement of CAD-RADS in the DLNR image was excellent (0.87, 95% confidence interval = 0.77-0.99) with original CCTAs., Conclusion: Our DLNR method supervised by 4DNR significantly reduced the image noise of CCTAs without affecting the assessment of coronary stenosis.

Reliable in vitro to in vivo translation of cytochrome P450 (CYP) 3A4 induction potential is essential to support risk mitigation for compounds during pharmaceutical discovery and development. In this study, a linear correlation of CYP3A4 mRNA induction potential in human hepatocytes with the respective pregnane-X receptor (PXR) activation in a reporter gene assay using DPX2 cells was successfully demonstrated for 13 clinically used drugs. Based on this correlation, using rifampicin as a positive control, the magnitude of CYP3A4 mRNA induction for 71 internal compounds at several concentrations up to 10 µ M ( n = 90) was predicted within 2-fold error for 64% of cases with only a few false positives (19%). Furthermore, the in vivo area under the curve reduction of probe CYP substrates was reasonably predicted for eight marketed drugs (carbamazepine, dexamethasone, enzalutamide, nevirapine, phenobarbital, phenytoin, rifampicin, and rufinamide) using the static net effect model using both the PXR activation and CYP3A4 mRNA induction data. The liver exit concentrations were used for the model in place of the inlet concentrations to avoid false positive predictions and the concentration achieving twofold induction (F2) was used to compensate for the lack of full induction kinetics due to cytotoxicity and solubility limitations in vitro. These findings can complement the currently available induction risk mitigation strategy and potentially influence the drug interaction modeling work conducted at clinical stages. SIGNIFICANCE STATEMENT: The established correlation of CYP3A4 mRNA in human hepatocytes to PXR activation provides a clear cut-off to identify a compound showing an in vitro induction risk, complementing current regulatory guidance. Also, the demonstrated in vitro-in vivo translation of induction data strongly supports a clinical development program although limitations remain for drug candidates showing complex disposition pathways, such as involvement of auto-inhibition/induction, active transport and high protein binding., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

The management of skin wound healing problems is a public health issue in which traditional herbal medicines could play a determining role. Kampo medicine, with three traditionally used ointments, provides interesting solutions for these dermatological issues. These ointments named Shiunkō , Chuōkō , and Shinsen taitsukō all have in common a lipophilic base of sesame oil and beeswax from which herbal crude drugs are extracted according to several possible manufacturing protocols. This review article brings together existing data on metabolites involved in the complex wound healing process. Among them are representatives of the botanical genera Angelica , Lithospermum , Curcuma , Phellodendron , Paeonia , Rheum , Rehmannia , Scrophularia , or Cinnamomum . Kampo provides numerous metabolites of interest, whose content in crude drugs is very sensitive to different biotic and abiotic factors and to the different extraction protocols used for these ointments. If Kampo medicine is known for its singular standardization, ointments are not well known, and research on these lipophilic formulas has not been developed due to the analytical difficulties encountered in biological and metabolomic analysis. Further research considering the complexities of these unique herbal ointments could contribute to a rationalization of Kampo's therapeutic uses for wound healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Paul-Traversaz, Umehara, Watanabe, Rachidi, Sève and Souard.)

Background: The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures in participating medical institutions nationwide and is intended to be used for promotion of AMR measures in participating facilities and their communities. This multicenter study aimed to determine the usefulness of the J-SIPHE system for evaluating the correlation between antibiotic use and antibiotic resistance in Hokkaido, Japan., Methods: Data on antibiotic use and detection rate of major resistant Gram-negative bacteria at 19 hospitals in 2020 were collected from the J-SIPHE system, and data correlations were analyzed using JMP Pro., Results: The detection rate of carbapenem-resistant Pseudomonas aeruginosa was significantly positively correlated with carbapenem use (Spearman's ρ = 0.551; P = .015). There were significant positive correlations between the detection rate of fluoroquinolone-resistant Escherichia coli and the use of piperacillin/tazobactam, carbapenems, and quinolones [ρ = 0.518 (P = .023), ρ = 0.76 (P < .001), and ρ = 0.502 (P = .029), respectively]., Conclusions: This is the first multicenter study to investigate the correlation between antibiotic use and antibiotic resistance using the J-SIPHE system. The results suggest that using this system may be beneficial for promoting AMR measures., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Drug-induced liver injury (DILI) is a major cause of market withdrawal or drug-development discontinuation because of safety concerns. In this study, we focused on drug-induced cholestasis (DIC) to establish an in vitro cytotoxicity test system and analyze its sensitivity using two-dimensional (2-D) cultured HepaRG cells and 12 types of bile acids (BAs) present in the human serum. First, to detect the cytotoxicity associated with cholestasis effectively, non-toxic BA concentrations were investigated and determined to be 100-fold the human serum value (455 μM total BAs). Next, the cytotoxicity of 31 compounds that can inhibit the bile acid export pump (BSEP) and were categorized as no-DILI-concern, less-DILI-concern, and most-DILI-concern was examined. None of the no-DILI-concern compounds yielded cytotoxicity, whereas almost all less-DILI-concern compounds (with the exception of simvastatin) and most-DILI-concern compounds (with the exception of bosentan) exhibited cytotoxicity. An investigation of the cause of cytotoxicity using 3 H-taurocholic acid revealed that most-DILI-concern and less-DILI-concern compounds, but not no-DILI-concern compounds, triggered the accumulation of radioactivity in the cell lysates. Thus, the onset of cytotoxicity seemed to be associated with cholestasis. The established HepaRG cytotoxicity assessment system (sensitivity of 89%, specificity of 100%, and accuracy of 97%) was mostly superior to the C ss /BSEP IC 50 (> 0.1) assessment system (sensitivity of 83%, specificity of 100%, and accuracy of 72%). Therefore, the assay method using 2-D cultured HepaRG cells and 12 BAs established here can be widely applicable as a model for the in vitro potential assessment of DIC.

Background: It is unclear whether deep-learning-based super-resolution technology (SR) or compressed sensing technology (CS) can accelerate magnetic resonance imaging (MRI) ., Purpose: To compare SR accelerated images with CS images regarding the image similarity to reference 2D- and 3D gradient-echo sequence (GRE) brain MRI., Material and Methods: We prospectively acquired 1.3× and 2.0× faster 2D and 3D GRE images of 20 volunteers from the reference time by reducing the matrix size or increasing the CS factor. For SR, we trained the generative adversarial network (GAN), upscaling the low-resolution images to the reference images with twofold cross-validation. We compared the structural similarity (SSIM) index of accelerated images to the reference image. The rate of incorrect answers of a radiologist discriminating faster and reference image was used as a subjective image similarity (ISM) index., Results: The SR demonstrated significantly higher SSIM than the CS (SSIM=0.9993-0.999 vs. 0.9947-0.9986; P  < 0.001). In 2D GRE, it was challenging to discriminate the SR image from the reference image, compared to the CS (ISM index 40% vs. 17.5% in 1.3×; P  = 0.039 and 17.5% vs. 2.5% in 2.0×; P  = 0.034). In 3D GRE, the CS revealed a significantly higher ISM index than the SR (22.5% vs. 2.5%; P  = 0.011) in 2.0 × faster images. However, the ISM index was identical for the 2.0× CS and 1.3× SR (22.5% vs. 27.5%; P  = 0.62) with comparable time costs., Conclusion: The GAN-based SR outperformed CS in image similarity with 2D GRE for MRI acceleration. In addition, CS was more advantageous in 3D GRE than SR.

Therapy for patients of metastatic breast cancer based on palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved in Japan. However, the risk factors for palbociclib-induced severe neutropenia in Japanese patients are rarely reported. Hence, the present study is aimed to identify the risk factors for adverse events requiring palbociclib dose reduction or discontinuation, and to identify the factors necessary to identify a more stable strategy for treatment continuation. This retrospective cohort analysis included patients with advanced breast cancer treated with 125 mg/d palbociclib. We demonstrated that severe neutropenia required significant dose reduction or therapy cessation. Most (77%) of the patients had severe neutropenia within the three courses. Risk factors for grade 3 or higher included low neutrophil counts (< 3250 /µL) before treatment [odds ratio (OR) = 9.10, 95% confidence interval (CI) (2.80-29.41), p < 0.001] and high age-adjusted Charlson comorbidity index (> 9) [OR = 1.64, 95% CI (1.09-2.48), p = 0.018]. Thus, low baseline neutrophil counts and high values for Age-adjusted Charlson comorbidity index are prospective predictive markers for palbociclib-induced severe neutropenia.

Purpose: Japan, with an increasing number of elderly people needing long-term care in a super-aged society, urgent needs to develop the clinical guidelines on implant maintenance for elderly people with declining independence. The purpose is to categorize the troubles encountered in the care of patients with dental implants and to indicate actual practices and points of note., Methods: From the members of the Japanese Society of Oral Implantology, 12 expert panelists who were experienced with many problems of implant maintenance during dental visits and were familiar with their solutions were selected. Through repeated discussions in the many panel meetings, the problems of implant maintenance during dental visits were distilled., Results: During a dental visit, the oral cavity, general conditions, and background of elderly patients who cannot orally care for themselves must be grasped, and medical staff, care managers, and patients should understand the changes in these factors as time goes by. The solutions and responses that can be made differ greatly depending on the medical care facilities, the environment, differences in the experience of medical staff, and the patient's background. Thus, it is necessary to select safe treatments appropriate to each situation., Conclusions: This paper features many opinions based on clinical experiences. However, clinical guidelines on implant management during dental visits should be formulated in the future based on the accumulation of evidence through the implementation of clinical research., (© 2022. The Author(s).)

The International Consortium for Innovation and Quality (IQ) Physiologically Based Pharmacokinetic (PBPK) Modeling Induction Working Group (IWG) conducted a survey across participating companies around general strategies for PBPK modeling of induction, including experience with its utility to address various questions, regulatory interactions, and regulatory acceptance. The results highlight areas where PBPK modeling is used with high confidence and identifies opportunities where confidence is lower and further evaluation is needed. To enhance the survey results, the PBPK-IWG also collected case studies and analyzed recent literature examples where PBPK models were applied to predict CYP3A induction-mediated drug-drug interactions. PBPK modeling of induction has evolved and progressed significantly, proving to have great potential to accelerate drug discovery and development. With the aim of enabling optimal use for new molecular entities that are either substrates and/or inducers of CYP3A, the PBPK-IWG proposes initial workflows for PBPK application, discusses future trends, and identifies gaps that need to be addressed., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Background To improve myocardial delayed enhancement (MDE) CT, a deep learning (DL)-based post hoc denoising method supervised with averaged MDE CT data was developed. Purpose To assess the image quality of denoised MDE CT images and evaluate their diagnostic performance by using late gadolinium enhancement (LGE) MRI as a reference. Materials and methods MDE CT data obtained by averaging three acquisitions with a single breath hold 5 minutes after the contrast material injection in patients from July 2020 to October 2021 were retrospectively reviewed. Preaveraged images obtained in 100 patients as inputs and averaged images as ground truths were used to supervise a residual dense network (RDN). The original single-shot image, standard averaged image, RDN-denoised original (DL original ) image, and RDN-denoised averaged (DL ave ) image of holdout cases were compared. In 40 patients, the CT value and image noise in the left ventricular cavity and myocardium were assessed. The segmental presence of MDE in the remaining 40 patients who underwent reference LGE MRI was evaluated. The sensitivity, specificity, and accuracy of each type of CT image and the improvement in accuracy achieved with the RDN were assessed using odds ratios (ORs) estimated with the generalized estimation equation. Results Overall, 180 patients (median age, 66 years [IQR, 53-74 years]; 107 men) were included. The RDN reduced image noise to 28% of the original level while maintaining equivalence in the CT values ( P < .001 for all). The sensitivity, specificity, and accuracy of the original images were 77.9%, 84.4%, and 82.3%, of the averaged images were 89.7%, 87.9%, and 88.5%, of the DL original images were 93.1%, 87.5%, and 89.3%, and of the DL ave images were 95.1%, 93.1%, and 93.8%, respectively. DL original images showed improved accuracy compared with the original images (OR, 1.8 [95% CI: 1.2, 2.9]; P = .011) and DL ave images showed improved accuracy compared with the averaged images (OR, 2.0 [95% CI: 1.2, 3.5]; P = .009). Conclusion The proposed denoising network supervised with averaged CT images reduced image noise and improved the diagnostic performance for myocardial delayed enhancement CT. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Vannier and Wang in this issue.

General anesthetic agents can change the shivering threshold. Sevoflurane and desflurane are widely used as inhalational anesthetics and have also been reported to lower the shivering threshold in a dose-dependent manner. Although the comparison of postoperative shivering (POS) between total intravenous anesthesia and inhalational anesthesia has been reported, there have been no reports on a direct comparison between sevoflurane and desflurane anesthesia and the occurrence of POS in open abdominal surgery. After obtaining approval from the Ethics Review Committee (2020-261), 683 adult patients who underwent open radical surgery for uterine, cervical, or pancreatic cancer under general anesthesia using inhalational anesthetics at Kyushu University hospital between December 2012 and March 2020 were included in this retrospective study. The odds ratio (OR) for the occurrence of POS between the two groups (sevoflurane and desflurane) was calculated. Multivariable-adjusted analysis was performed using possible factors affecting POS. Furthermore, propensity score (PS) matching was conducted using these factors. The multivariable-adjusted OR for the occurrence of shivering in the desflurane group (62 occurrences/356 patients) was 1.06 (95% confidence interval [CI]: 0.69-1.62, p  = 0.79) compared with the sevoflurane group (77/327, reference). Similarly, after PS matching, the crude OR for the occurrence of shivering in the desflurane group (47/210) was 1.09 (95% CI: 0.68-1.75, p  = 0.72) compared with the sevoflurane group (44/210, reference). Similar results were obtained in the stratified analysis by sex and age. The occurrence of POS is not different between sevoflurane and desflurane anesthesia.

The in vivo half-life is a key property of every drug molecule, as it determines dosing regimens, peak-to-trough ratios and often dose. However, half-life optimization can be challenging due to its multifactorial nature, with in vitro metabolic turnover, plasma protein binding and volume of distribution all impacting half-life. We here propose that the medicinal chemistry design parameter Lipophilic Metabolism Efficiency (LipMetE) can greatly simplify half-life optimization of neutral and basic compounds. Using mathematical transformations, examples from preclinical GABA A projects and clinical compounds with human pharmacokinetic data, we show that LipMetE is directly proportional to the logarithm of half-life. As the design parameter LipMetE can be swiftly calculated using the readily available parameters LogD, intrinsic clearance and fraction unbound in human liver microsomes or hepatocytes, this approach enables rational half-life optimization from the early stages of drug discovery projects., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery to clinical development to post-marketing activities. Development of standards for how these models are constructed, assessed, and communicated is of active interest to the modeling community and regulators but is complicated by the wide variability in the structures and intended uses of the underlying models and the diverse expertise of QSP modelers. With this in mind, the IQ Consortium conducted a survey across the pharmaceutical/biotech industry to understand current practices for QSP modeling. This article presents the survey results and provides insights into current practices and methods used by QSP practitioners based on model type and the intended use at various stages of drug development. The survey also highlights key areas for future development including better integration with statistical methods, standardization of approaches towards virtual populations, and increased use of QSP models for late-stage clinical development and regulatory submissions., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

RO7119929 is being developed as an orally administered prodrug of the TLR7-specific agonist and active drug, RO7117418, for the treatment of patients with solid tumours.In this publication, we present a case study wherein the human pharmacokinetics and pharmacological active dose were prospectively predicted following oral administration of the prodrug.A simple translational pharmacokinetic-pharmacodynamic strategy was applied to predict the pharmacological active dose of the prodrug in human. In vivo studies in monkey showed that an unbound plasma exposure of active drug of 1.5 ng/mL elicited secretion of key serum pharmacodynamic cytokine and chemokine biomarkers in monkey. This threshold of 1.5 ng/mL was close to the minimum effective concentration of active drug required to induce cytokine secretion in human peripheral blood mononuclear cells (3 ng/mL).Measured in vitro physicochemical and biochemical properties of the prodrug and active drug were applied as input parameters in physiologically based pharmacokinetic models to predict the pharmacokinetics of active drug after oral dosing of the prodrug in humans. Then, using the PBPK model, a dose which delivered an unbound plasma Cmax in line with the target pharmacodynamic threshold of 1.5 ng/mL was found. This defined the lowest pharmacologically active dose as 3 mg.The prodrug entered the clinic in 2020 in patients with primary or secondary liver cancers. Clear pharmacodynamic, transient, and dose-dependent cytokine induction was observed at prodrug doses > 1 mg.

Background: Postreperfusion syndrome (PRS) after portal vein reperfusion during liver transplantation (LT) has been reported to cause rapid hemodynamic changes and is associated with a prolonged postoperative hospital stay, renal failure, and increased mortality. Although there are some reports on risk factors for PRS in brain-dead donor LT, there are a few reports on those in living donor LT. Therefore, we retrospectively reviewed the factors associated with PRS to contribute to the anesthetic management so as to reduce PRS during living donor LT., Methods: After approval by the ethics committee of our institution, 250 patients aged ≥20 years who underwent living donor LT at our institution between January 2013 and September 2018 were included in the study. A decrease in mean arterial pressure of ≥30% within 5 minutes after portal vein reperfusion was defined as PRS, and estimates and odds ratio (OR) for PRS were calculated using logistic regression. The backward method was used for variable selection in the multivariable analysis., Results: Serum calcium ion concentration before reperfusion (per 0.1 mmol/L increase; OR, 0.74; 95% confidence interval (CI), 0.60-0.95; P < .001), preoperative echocardiographic left ventricular end-diastolic diameter (per 1-mm increase: OR, 0.90; 95% CI, 0.85-0.95; P < .001, men [versus women: OR, 2.45; 95% CI, 1.26-4.75; P = .008]), mean pulmonary artery pressure before reperfusion (restricted cubic spline, P = .003), anhepatic period (restricted cubic spline, P = .02), and graft volume to standard liver volume ratio (restricted cubic spline, P = .03) were significantly associated with PRS., Conclusions: In living donor LT, male sex and presence of small left ventricular end-diastolic diameter, large graft volume, and long anhepatic period are associated with PRS, and a high calcium ion concentration and low pulmonary artery pressure before reperfusion are negatively associated with PRS., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

This study aimed to investigate whether renin-angiotensin system inhibitors (RAS-I) have an advantage over calcium channel blockers (CCB) for suppression of proteinuria in hypertensive patients with gastric cancer receiving ramucirumab (RAM) treatment. Adult Japanese patients with gastric cancer who were outpatients at Asahikawa Medical University Hospital, National Hospital Organization Hokkaido Cancer Center, and Iwate Medical University Hospital between July 1, 2015, and March 31, 2021, were included in this study. Of these patients, those who had received first-time RAM treatment, and those treated with antihypertensive agents including RAS-I or a CCB at initial RAM administration were included. A total of 36 patients were analyzed in this study. Of these patients, 17 patients were classified into the RAS-I group and the remaining 19 into the CCB group. After 12 weeks of RAM administration, the prevalence of proteinuria in the RAS-I group was significantly lower than that in the CCB group. Additionally, Kaplan-Meier analysis showed that the cumulative occurrence of proteinuria in the RAS-I group over 12 weeks following RAM administration was significantly lower than that in the CCB group. Furthermore, simulation of the time course of RAM blood concentrations based on the O'Brien model showed that there may not be differences in the RAM blood concentration profiles over 12 weeks between the two groups. RAS-I may have an advantage over CCB for suppressing proteinuria in hypertensive patients with gastric cancer treated with blood pressure antihypertensive agents. Our results provide useful information to healthcare professionals involved in the administration of RAM treatment., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Chiba et al.)

The spatial resolution of fMRI is relatively poor and improvements are needed to indicate more specific locations for functional activities. Here, we propose a novel scheme, called Static T2*WI-based Subject-Specific Super Resolution fMRI (STSS-SRfMRI), to enhance the functional resolution, or ability to discriminate spatially adjacent but functionally different responses, of fMRI. The scheme is based on super-resolution generative adversarial networks (SRGAN) that utilize a T2*-weighted image (T2*WI) dataset as a training reference. The efficacy of the scheme was evaluated through comparison with the activation maps obtained from the raw unpreprocessed functional data (raw fMRI). MRI images were acquired from 30 healthy volunteers using a 3 Tesla scanner. The modified SRGAN reconstructs a high-resolution image series from the original low-resolution fMRI data. For quantitative comparison, several metrics were calculated for both the STSS-SRfMRI and the raw fMRI activation maps. The ability to distinguish between two different finger-tapping tasks was significantly higher [p = 0.00466] for the reconstructed STSS-SRfMRI images than for the raw fMRI images. The results indicate that the functional resolution of the STSS-SRfMRI scheme is superior, which suggests that the scheme is a potential solution to realizing higher functional resolution in fMRI images obtained using 3T MRI., (© 2022. The Author(s).)

Estimation of the fraction of a drug metabolized by individual hepatic CYP enzymes relative to hepatic metabolism (fm,CYP) or total clearance h as been challenging for low turnover compounds due to insufficient resolution of the intrinsic clearance (CLint) measurement in vitro and difficulties in quantifying the formation of low abundance metabolites. To overcome this gap, inhibition of drug depletion or selective metabolite formation for 7 marker CYP substrates was investigated using chemical inhibitors and a micro-patterned hepatocyte coculture system (HepatoPac). The use of 3 μ M itraconazole was successfully validated for estimation of fm,CYP3A4 by demonstration of fm values within a 2-fold of in vivo estimates for 10 out of 13 CYP3A4 substrates in a reference set of marketed drugs. Other CYP3A4 inhibitors (ketoconazole and posaconazole) were not optimal for estimation of fm,CYP3A4 for low turnover compounds due to their high CLint. The current study also demonstrated that selective inhibition sufficient for fm calculation was achieved by inhibitors of CYP1A2 (20 μ M furafylline), CYP2C8 (40 μ M montelukast), CYP2C9 (40 μ M sulfaphenazole), CYP2C19 [3 μ M (-)N-3-benzyl-phenobarbital], and CYP2D6 (5 μ M quinidine). Good estimation of fm,CYP2B6 was not possible in this study due to the poor selectivity of the tested inhibitor (20 μ M ticlopidine). The approach verified in this study can result in an improved fm estimation that is aligned with the regulatory agencies' guidance and can support a victim drug-drug interaction risk assessment strategy for low clearance discovery and development drug candidates. SIGNIFICANCE STATEMENT: Successful qualification of a chemical inhibition assay for estimation of fraction metabolized requires chemical inhibitors that retain sufficient unbound concentrations over time in the incubates. The current cocultured hepatocyte assay enabled estimation of fraction metabolized, especially by CYP3A4, during the drug discovery phase where metabolite quantification methods may not be available. The method enables the assessment of pharmacokinetic variability and victim drug-drug interaction risks due to enzyme polymorphism or inhibition/induction with more confidence, especially for low clearance drug candidates., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Idasanutlin is a potent inhibitor of the p53-MDM2 interaction that enables reactivation of the p53 pathway, which induces cell cycle arrest and/or apoptosis in tumor cells expressing functional p53. It was investigated for the treatment of solid tumors and several hematologic indications such as relapsed/refractory acute myeloid leukemia, polycythemia vera, or non-Hodgkin lymphoma. For safety reasons, it cannot be given in healthy volunteers for drug-drug interaction (DDI) explorations. This triggered the need for in silico explorations on top of the one available CYP3A clinical DDI study with posaconazole in solid tumor patients. Idasanutlin's clearance is dependent on CYP3A4/2C8 forming its major circulating metabolite M4, with contributions from UGT1A3 and biliary excretion. Idasanutlin and M4 have low permeability, very low clearance, and extremely low unbound fraction in plasma (<0.001), which makes in vitro data showing inhibition on CYP3A4/2C8 enzymes challenging to translate to clinical relevance. Physiologically-based pharmacokinetic models of idasanutlin and M4 have been established to simulate perpetrator and victim DDI scenarios and to evaluate whether further DDI studies in oncology patients are necessary. Modeling indicated that idasanutlin and M4 would show no or weak clinical inhibition of selective CYP3A4/2C8 substrates. Co-administered strong CYP3A and CYP2C8 inhibitors might lead to weak or moderate idasanutlin exposure increases, and the strong inducer rifampicin might cause moderate exposure reduction. As the simulated idasanutlin systemic exposure changes would be within the range of observed intrinsic variability, the target population can take co-medications that are either CYP2C8/3A4 inhibitors or weak/moderate CYP2C8/3A4 inducers without dose adjustment. SIGNIFICANCE STATEMENT: Clinical trials for idasanutlin are restricted to cancer patients, which imposes practical, scientific, and ethical challenges on drug-drug interaction investigations. Furthermore, idasanutlin and its major circulating metabolite have very challenging profiles of absorption, distribution, metabolism and excretion including high protein binding, low permeability and a combination of different elimination pathways each with extremely low clearance. Nonetheless, physiologically-based pharmacokinetic models could be established and applied for drug-drug interaction risk assessment and were especially useful to provide guidance on concomitant medications in patients., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios can indicate poor disease prognosis and are inflammation markers. We investigated the role of NLR and PLR as effective predictive markers of immune-related adverse event (irAE) onset in patients treated with nivolumab., Methods: We retrospectively analysed 73 gastric and renal cancer patients treated with nivolumab at the Hokkaido Cancer Centre from January 2017 to June 2020. NLR and PLR were calculated at the initiation of nivolumab treatment and irAE onset. We identified the risk factors for Grade 3-4 irAE onset using NLR, PLR, sex, cancer type, and age. Overall survival (OS) and progression free survival (PFS) were calculated from the initiation of nivolumab treatment to the date of death or censored at last follow-up., Results: Among the 73 patients included, 17 (18%) had at least one grade3-4 irAE. Multivariable logistic regression analyses revealed that pretreatment NLR<4.3 was significantly associated with a reduced risk for onset of grade3-4 irAEs, whereas rate of NLR change after treatment, ΔNLR>120% was significantly associated with an increased risk., Conclusions: NLR is an effective marker for prognosis and onset of grade 3-4 irAEs.

Background Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC 50 2 μM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC 50 1.33 μM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib C max and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib C max and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although C max decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased C max by 21%. Single dose entrectinib increased digoxin AUC and C max by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered., (© 2021. The Author(s).)