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. Therefore, many medical facilities have been implementing infection control programs based on antimicrobial stewardship to prevent nosocomial infections and drug-resistant strains. Studies detailing pharmacometrics for these antibiotics have been reported to elucidate the pharmacokinetic and pharmacodynamic properties, to determine significant factors influencing variabilities between individuals, and to develop target concentration interventions and dosing regimens for adults, the elderly, patients with renal insufficiency including those on continuous renal replacement therapies, patients with low body weight, obese patients, and pediatric patients. This review presents the details of our recent research on the optimal dosing design of antimicrobial agents for the treatment of MRSA infection based on hospital pharmacometrics. In addition, the prospect of using modeling and simulation has shown major advantages in supporting dosing regimen selection.
Autophagy is an intracellular degradation pathway conserved in eukaryotes. Among core autophagy-related (Atg) proteins, mammalian Atg9A is the sole multi-spanning transmembrane protein, and both of ...its N- and C-terminal domains are exposed to the cytoplasm. It is known that Atg9A travels through the trans-Golgi network (TGN) and the endosomal system under nutrient-rich conditions, and transiently localizes to the autophagosome upon autophagy induction. However, the significance of Atg9A trafficking for autophagosome formation remains elusive. Here, we identified sorting motifs in the N-terminal cytosolic stretch of Atg9A that interact with the adaptor protein AP-2. Atg9A with mutations in the sorting motifs could not execute autophagy and was abnormally accumulated at the recycling endosomes. The combination of defects in autophagy and Atg9A accumulation in the recycling endosomes was also found upon the knockdown of TRAPPC8, a specific subunit of the TRAPPIII complex. These results show directly that the trafficking of Atg9A through the recycling endosomes is an essential step for autophagosome formation.
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. A single-center retrospective observational study was conducted at Tokyo Women’s Medical University, Medical Center East. The study population consisted of adult patients aged >20 years who commenced warfarin with a prothrombin time-international normalized ratio (PT-INR) from June 2015 to June 2019. The published K-PD model modified by Wright and Duffull was assessed using prediction-corrected visual predictive checks, focusing on clinical characteristics, including age, renal function, and individual prediction error. The external dataset included 232 patients who received an initial warfarin daily dose of 3.2 ± 1.28 mg with 2278 PT-INR points (median range follow-up period of 23 d 7–28). Prediction-corrected visual predictive checks carried a propensity for underprediction. Additionally, age >60 years, body mass index ≤25 kg/m2, and estimated glomerular filtration rate ≤60 mL/min/1.73 m2 had a pronounced tendency to underpredict PT-INR. However, Bayesian prediction using four prior observations reduced underprediction. To improve the prediction performance of these special populations, further studies are required to construct a model to predict warfarin dose requirements in Japanese patients.
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. Specifically, the computational design approach was applied to optimize the blood sampling schedule for a bioequivalence (BE) study in pediatrics and optimize the allocation of dose groups for a dose‐finding study. The GA could reduce the number of blood collection points from 15 (typical standard) to seven points without meaningful impact on the accuracy and precision of the pharmacokinetic estimation for the pediatric BE study. For the dose‐finding study, up to 10% reduction of the total number of required subjects from the standard design could be achieved. The GA also created a design that would lead to a drastic reduction of the required number of subjects in the placebo arm while keeping the total number of subjects at a minimum level. These results indicated the potential usefulness of the computational clinical study design approach for innovative drug development.
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 53.4 ± 11.5 µg/dL. More than half of the patients (67%) had zinc deficiency (<60 µg/dL), whereas 33% had subclinical zinc deficiency (60–80 µg/dL). The median increase in serum zinc level per ZAH tablet (25 mg) was 1.00 µg/dL. Based on the cutoff value, two groups were identified: slight increase (<1.00 µg/dL) and marked increase (≥1.00 µg/dL) groups; the difference between the two groups was significant (0.57 ± 0.22 µg/dL, n = 39 vs. 1.68 ± 0.70 µg /dL, n = 40; p < 0.0001, Wilcoxon rank sum test). Logistic regression analysis using total zinc dose, serum albumin level, impaired renal function, and diuretics as multivariate variables revealed a significant difference in total zinc dose (total number of tablets per 25 mg tablet: odds ratio 1.056, 95% confidence interval 1.019–1.095, p = 0.003). A significant increase in serum zinc levels was observed in the group with a total zinc dose of less than 1000 mg. The results suggest that an increasing trend in total zinc dose is associated with a low increase in serum zinc levels. Therefore, for the treatment of zinc deficiency in elderly inpatients, serum zinc levels need to be measured once, at a total dose of 1000 mg after initiation of ZAH.
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.
Methods
PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUC
PAT
) was evaluated against the reference AUC (AUC
REF
) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUC
BM-P
) calculated using an evaluated available software with clinical data.
Results
Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept −15.57, median AUC
PAT
/AUC
REF
0.93 range 0.81–1.24), where only one estimation (6%) was out of the predetermined acceptable range of 0.8–1.2. Employment of only a trough concentration was more biased (AUC
PAT
/AUC
REF
range 0.73–1.30 for 11 h, AUC
PAT
/AUC
REF
range 0.62–1.40 for 23 h). In comparison with the evaluated software, AUC
PAT
was not biased against the AUC
BM-P
(slope 1.04, intercept −15.80, median AUC
PAT
/AUC
BM-P
1.00 range 0.86–1.10).
Conclusions
The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin.
The aims of the present study were (a) to evaluate the pharmacokinetics of linezolid, and (b) to assess the toxicity and clinical efficacy of linezolid in Japanese pediatric patients.
Routine ...clinical data including serum linezolid total and unbound concentrations were collected from 15 pediatric patients (0–13 years old). Pharmacokinetics of linezolid was assumed to follow one-compartment with the first-order absorption model. The relationship between risk for thrombocytopenia and linezolid concentrations, and the variations in C-reactive protein (CRP) concentrations and body temperatures were evaluated as clinical efficacy assessment.
Body weight (WT) and maturation of body function were significant covariates for pharmacokinetics of linezolid in pediatric patients. The elimination half-life of linezolid in a pediatric patient with a WT of 9.9 kg and age of 24 months (median of this study) was 3.0 h. Thrombocytopenia was detected in three patients (21.4%), and the minimum concentrations (Cmin) in these patients were significantly higher than those in patients without thrombocytopenia (P < 0.05). The CRP concentrations decreased more than 50% in all pediatric patients after the treatment with linezolid, however body temperatures at the end of treatment were higher than 37.5 °C in 6 patients (42.9%).
Although dose adjustment based on body size was performed for pediatric patients, thrombocytopenia was detected in 21.4% of pediatric patients, and higher Cmin was associated with the risk of thrombocytopenia. These results encourage the implementation of individual dose adjustment based on linezolid serum concentrations for safe and appropriate treatment with linezolid.
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). The estimated CL value from the ANN were substituted into the one‐compartment with one‐order absorption model, the concentrations were calculated, and the parameters of ANN were updated by the back‐propagation method. Kernel SHAP was applied to the trained model and the SHAP value of each input was calculated. The root mean squared error for the PopPK model and the ANN‐PK model were 41.1 and 31.0 ng/ml, respectively. The goodness of fit plots for the ANN‐PK model represented more convergence to y = x compared with that for the PopPK model, with good model performance for the ANN‐PK model. The most influential factors on CL output were age and body weight from the evaluation using Kernel SHAP, and these factors were incorporated into the PopPK model as the significant covariates of CL. The ANN‐PK model could handle time‐series data and showed higher prediction accuracy then the conventional PopPK model, and the scientific validity for the model could be evaluated by applying SHAP.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
A black‐box property of an artificial neural network (ANN) decreases the scientific confidence of the model, and making it difficult to utilize the ANN in the medical field. Moreover, difficulty in handling the time‐series data is a significant problem for applying the ANN for pharmacometrics study.
WHAT QUESTION DID THIS STUDY ADDRESS?
How can we apply the ANN for predicting the time‐series pharmacokinetics (PKs) , and confirm the scientific validity of the ANN model?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Using the ANN in combination with a conventional compartment (ANN‐PK) model enabled to handle the time‐series PK data, and the predicting performance of the model was higher than that of the population PK model. Furthermore, we could evaluate the scientific validity of the ANN model by applying the Shapley additive explanations.
HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?
We expect that our study will contribute to develop the interpretable ANN model, which can predict the time‐series PKs, drug efficacies, and side effects with high prediction performance.
Clock genes encoding transcription factors that regulate circadian rhythms may inform chronomodulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side ...effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here, we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects and that the
gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chronomodulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies.
.
Linezolid is an oxazolidinone antibiotic that effectively treats methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Since rifampicin induces other ...antibiotic effects, it is combined with linezolid in therapeutic regimes. However, linezolid blood concentrations are reduced by this combination, which increases the risk of the emergence of antibiotic-resistant bacteria. We herein demonstrated that the combination of linezolid with rifampicin inhibited its absorption and promoted its elimination, but not through microsomal enzymes. Our results indicate that the combination of linezolid with rifampicin reduces linezolid blood concentrations via metabolic enzymes.
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