Pharmacokinetic Model of Drug Interaction of Tacrolimus with Combined Administration of CYP3A4 Inhibitors Voriconazole and Clarithromycin After Bone Marrow Transplantation.

Background And Objectives: A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes.

Methods: This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated.

Challenges of pediatric pharmacotherapy: A narrative review of pharmacokinetics, pharmacodynamics, and pharmacogenetics.

Purpose: Personalized pharmacotherapy, including for the pediatric population, provides optimal treatment and has emerged as a major trend owing to advanced drug therapeutics and diversified drug selection. However, it is essential to understand the growth and developmental characteristics of this population to provide appropriate drug therapy. In recent years, clinical pharmacogenetics has accumulated knowledge in pediatric pharmacotherapy, and guidelines from professional organizations, such as the Clinical Pharmacogenetics Implementation Consortium, can be consulted to determine the efficacy of specific drugs and the risk of adverse effects.

Comparison of the efficacy of anti-diabetic medications as add-on to metformin in type 2 diabetes mellitus from a real-world database.

Background: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A levels.

Relationship between prolonged gestation and nifedipine pharmacokinetics in long-term tocolysis.

In this study, we examined the pharmacokinetics of nifedipine and investigated the maternal and foetal background factors that prolong pregnancy in pregnant women undergoing long-term tocolysis. This prospective observational study included 38 pregnant women hospitalised for threatened preterm labour and treated with nifedipine extended-release tablets in combination with an intravenous ritodrine infusion. Maternal plasma nifedipine concentrations were determined using high-performance liquid chromatography.

Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.

Aims: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function.

Methods: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme.

Effectiveness and Safety of Linezolid Versus Vancomycin, Teicoplanin, or Daptomycin against Methicillin-Resistant Bacteremia: A Systematic Review and Meta-Analysis.

Vancomycin (VCM) and daptomycin (DAP) are standard therapies for methicillin-resistant (MRSA) bacteremia, despite concerns regarding clinical utility and growing resistance. Linezolid (LZD) affords superior tissue penetration to VCM or DAP and has been successfully used as salvage therapy for persistent MRSA bacteremia, indicating its utility as a first-choice drug against MRSA bacteremia. In a systematic review and meta-analysis, we compared the effectiveness and safety of LZD with VCM, teicoplanin (TEIC), or DAP in patients with MRSA bacteremia.

Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis.

Background And Objective: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations.

Methods: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis.

Cases of Pediatric Pyelonephritis: A Single-Center Retrospective Study from an Extended-Spectrum β-Lactamase-Producing Escherichia coli Endemic Area in Japan.

Background: Extended-spectrum β-lactamase (ESBL)-producing has been increasingly recognized as the cause of upper urinary tract infection (UTI) in children. We have been using flomoxef at our department since 2017 as the first-line empiric therapy for children diagnosed with UTIs, and we avoid using carbapenems, which are considered the first-line treatment for ESBL-producing . However, reports on the use of flomoxef for UTIs are limited, especially for pediatric patients.

Computational design of clinical trials using a combination of simulation and the genetic algorithm.

Artificial intelligence (AI) has come to be used in various technological fields in recent years. However, there have been no reports of AI-designed clinical trials. In this study, we tried to develop study designs by a genetic algorithm (GA), which is an AI solution for combination optimization problems.

Efficacy of Zinc Acetate in the Treatment of Zinc Deficiency in Elderly Inpatients and Effect of Total Dose on Its Replacement Therapy.

We aimed to determine the efficacy of zinc acetate hydrate (ZAH) treatment for hypozincemia in elderly inpatients and to identify the factors affecting its therapeutic effect. We enrolled 79 patients with a mean age of 82 years. The mean serum zinc level before ZAH administration was 53.

External Evaluation of a Bayesian Warfarin Dose Optimization Based on a Kinetic-Pharmacodynamic Model.

Warfarin is a representative anticoagulant with large interindividual variability. The published kinetic-pharmacodynamic (K-PD) model allows the prediction of warfarin dose requirement in Swedish patients; however, its applicability in Japanese patients is not known. We evaluated the model's predictive performance in Japanese patients with various backgrounds and relationships using Bayesian parameter estimation and sampling times.

Development of a simple method for measuring tedizolid concentration in human serum using HPLC with a fluorescent detector.

The objective of the present study was to develop a method to measure tedizolid (TZD) concentration for studying target concentration intervention, pharmacokinetics, and pharmacodynamics of TZD. We established a high-performance liquid chromatography-fluorescence detector assay to measure the TZD concentration in serum for clinical application. Chromatographic separation was carried out on a 5 μm octadecyl silane hypersil column 150 mm × 4.

Hospital Pharmacometrics for Optimal Individual Administration of Antimicrobial Agents for Anti-methicillin-resistant Staphylococcus aureus Infected Patients.

Therapeutic drug monitoring and target concentration intervention based on population pharmacokinetic and pharmacodynamic models has been strongly recommended for anti-methicillin-resistant Staphylococcus aureus (MRSA) agents in order to provide appropriate antimicrobial chemotherapy to each individual patient, and pharmacokinetic and pharmacodynamic analyses in hospitalized patients have been actively conducted, as evidenced with vancomycin. Teicoplanin, daptomycin, and linezolid have been the most studied antibiotics, using population pharmacokinetics of patients with MRSA. Infections caused by MRSA have higher severity and fatality rates than other antimicrobial-susceptible infections.

An artificial neural network-pharmacokinetic model and its interpretation using Shapley additive explanations.

We developed a method to apply artificial neural networks (ANNs) for predicting time-series pharmacokinetics (PKs), and an interpretable the ANN-PK model, which can explain the evidence of prediction by applying Shapley additive explanations (SHAP). A previous population PK (PopPK) model of cyclosporin A was used as the comparison model. The patients' data were used for the ANN-PK model input, and the output by ANN was the clearance (CL).

Performance of Area under the Concentration-Time Curve Estimations of Vancomycin with Limited Sampling by a Newly Developed Web Application.

Purpose: Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation.

Classification Tree Analysis Based On Machine Learning for Predicting Linezolid-Induced Thrombocytopenia.

Linezolid-induced thrombocytopenia is related to linezolid exposure, baseline platelet count and patient background. Although the relationship usually reflects the time of onset of thrombocytopenia, if the platelet maturation process is taken into account, the platelet decrease can be considered to have started at the beginning of treatment. To predict linezolid-induced thrombocytopenia, classification and regression tree (CART) analysis based on machine learning has been applied to identify predictive factors and cutoff values.

External Evaluation of Population Pharmacokinetics and Pharmacodynamics in Linezolid-Induced Thrombocytopenia: The Transferability of Published Models to Different Hospitalized Patients.

Background: The objective of this study was to perform an external evaluation of published linezolid population pharmacokinetic and pharmacodynamic models, to evaluate the predictive performance using an independent data set. Another aim was to offer an elegant environment for display and simulation of both the concentration and platelet count after linezolid administration.

Methods: We performed a systematic literature search in PubMed for all studies evaluating the population pharmacokinetic and pharmacodynamic parameters of linezolid in patients and selected the models to be used for the external validation.

Evaluation of the relationship between linezolid exposure and hyponatremia.

Introduction: Aims of this study were (a) to assess the development ratio of hyponatremia during treatment with linezolid and (b) to evaluate the relationship between the risk of hyponatremia and linezolid exposure and patient background.

Method: Clinical data including linezolid serum concentrations and serum sodium values were collected at Toyama University Hospital and Kyorin University Hospital. Data from 89 patients were used for the analysis, and a nadir serum sodium level ≤130 mmol/L during the treatment with linezolid was defined as hyponatremia.

Pharmacokinetics and pharmacodynamics of daptomycin in a clinical setting.

We investigated achievement of a target 24-h area under the concentration-time curve to minimum inhibitory concentration ratio (AUC/MIC) ≥666 and the factors influencing this ratio in patients who received daptomycin (DAP) for infectious disease treatment in a clinical setting. The target AUC/MIC was obtained in 6 patients (35.3%) at a 4-6 mg/kg dose (Group) and in 4 (18.