Comparison of vancomycin area under the curve calculated based on Bayesian approach versus equation-based approach.

OBJECTIVE: Area under the curve (AUC)-based vancomycin dose adjustment is recommended to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. AUC estimation methods include Bayesian software programs and simple analytical equations. This study compared the AUC obtained using the Bayesian approach with that obtained using an equation-based approach. MATERIALS AND METHODS: Patients receiving intravenous vancomycin for MRSA infection were included. Peak and trough levels were measured for each patient on days 3, 7, and 10 post vancomycin dosing (day 1). AUC was calculated using software based on the Bayesian method (MwPharm Online) and an equation-based calculator, Stanford Health Care (SHC) calculator. RESULTS: The AUC estimated using MwPharm Online was similar to that estimated using the SHC calculator. The geometric mean ratio (GMR) and their 90% confidence intervals (90% CI) were 1.08 (1.05 - 1.11), 1.03 (0.99 - 1.07), and 0.99 (0.94 - 1.05) at days 3, 7, and 10, respectively. Furthermore, according to the software used, there were no significant differences in the proportions of patients in the categories "within" and "below or above" the AUC target range. Additionally, trough levels predicted by both software programs were lower than the observed ones. Still, there was no significant difference between the predicted and observed peak levels for both software programs on day 10. CONCLUSION: AUC calculated using the Bayesian software allows for calculation with samples at a non-steady state, can integrate covariates, and is interconvertible with that estimated using an equation-based calculator, which is simpler and relies on fewer assumptions. Therefore, either method can be used, considering each method's strengths and limitations.

Analysis of the immunostimulatory effects of cytokine-expressing internal ribosome entry site-based RNA adjuvants and their applications.

Developing new adjuvants that can effectively induce both humoral and cellular immune responses while broadening the immune response is of great value. In this study, we aimed to develop GM-CSF- or IL-18-expressing single-stranded RNA (ssRNA) adjuvants based on the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) and tested their efficacy in combination with ovalbumin (OVA) or inactivated influenza vaccines. Notably, cytokine-expressing RNA adjuvants increased the expression of antigen-presenting cell activation markers. Specifically, GM-CSF-expressing RNA adjuvants increased CD4+T cell responses, while IL-18-expressing RNA adjuvants increased CD8+T cell responses in mice when combined with OVA. In addition, cytokine-expressing RNA adjuvants increased the frequency of polyclonal T cells in combination with the influenza vaccine and reduced the clinical illness scores and weight loss of mice after viral challenge. Collectively, our results suggest that cytokine-expressing RNA adjuvants can be applied to protein-based or inactivated vaccines to increase their efficacy.

mRNA-HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV-mediated cancers via subcutaneous immunization.

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

Modeling Approach with Therapeutic Drug Monitoring Data to Describe Time Course of Clozapine Exposure and Positive and Negative Syndrome Scale Scores.

OBJECTIVE: The Positive and Negative Syndrome Scale (PANSS) is commonly used to assess the severity of the clinical symptoms of schizophrenia (SCZ). This study aimed to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model based on therapeutic drug monitoring (TDM) data to characterize the relationship between clozapine exposure and the PANSS scores in patients with SCZ. METHODS: TDM data for clozapine and PANSS scores from 45 patients with SCZ were included in this modeling analysis using NONMEM. Based on published data, intensive PK sampling data collected up to 12 hours postdose from 23 patients was incorporated into the PK data set to improve the fitting of absorption and disposition. For PD model development, the PANSS score was assessed at baseline, followed by 8 and 18 weeks after the initiation of clozapine dosing. Visual predictive check plots, the precision of parameter estimates, and decreases in the minimum objective function values were used for the model evaluation. RESULTS: A 2-compartment model with an absorption lag and a combined error model adequately described the PK of clozapine. The implementation of disease progression with placebo and drug effects improved the model's ability to describe the time course of the PANSS scores. In the final PK/PD model, Weibull and maximum effect (E max ) models were selected as disease progression models for the placebo and drug effect models, respectively. The model evaluation results supported the adequacy of the final model. CONCLUSIONS: A clozapine PK/PD model based on clinical settings adequately described the PANSS time course in patients with SCZ. These findings may aid the development of treatment strategies for patients with SCZ.

Measurement of craving among gamers with internet gaming disorder using repeated presentations of game videos: a resting-state electroencephalography study.

BACKGROUND: Internet gaming disorder (IGD) is receiving increasing attention owing to its effects on daily living and psychological function. METHODS: In this study, electroencephalography was used to compare neural activity triggered by repeated presentation of a stimulus in healthy controls (HCs) and those with IGD. A total of 42 adult men were categorized into two groups (IGD, n = 21) based on Y-IAT-K scores. Participants were required to watch repeated presentations of video games while wearing a head-mounted display, and the delta (D), theta (T), alpha (A), beta (B), and gamma (G) activities in the prefrontal (PF), central (C), and parieto-occipital (PO) regions were analyzed. RESULTS: The IGD group exhibited higher absolute powers of DC, DPO, TC, TPO, BC, and BPO than HCs. Among the IGD classification models, a neural network achieves the highest average accuracy of 93% (5-fold cross validation) and 84% (test). CONCLUSIONS: These findings may significantly contribute to a more comprehensive understanding of the neurological features associated with IGD and provide potential neurological markers that can be used to distinguish between individuals with IGD and HCs.

Exogenous protease influences protein digestibility, growth performance, and gut microflora in weanling pigs on a limited protein diet.

The study was conducted to evaluate the impact of dietary level of crude protein (CP) and protease supplementation on growth performance, digestibility of nutrients, intestinal morphology, and gut microbiota in weaning pigs. Three hundred cross-bred piglets (Duroc × Landrace × Yorkshire) were allotted to five dietary treatments on the basis of initial body weight (BW) and sex. Pigs were group-housed in pens with each treatment with 10 replicate pens with six pigs per pen. The treatments included a standard diet (STD), STD with 0.6% lower protein (STD0.6), STD with 0.6% lower protein and protease supplementation (Pro0.6), STD with 1.0% lower protein (STD1.0), STD with 1.0% lower protein and protease supplementation (Pro1.0). Results indicated a higher BW (p < 0.05) of piglets in the Pro0.6 group at days 0-42 compared to the STD0.6 and STD1.0 groups. The average daily gain was higher (p < 0.05) in the Pro0.6 treatments at days 0-42 compared to the STD0.6 and STD1.0. The gain to feed ratio was higher (p < 0.05) in the STD, and Pro0.6 groups compared to the STD0.6, Pro1.0 and the STD1.0 groups at days 0-42. Dry matter digestibility was lower (p < 0.05) in the STD1.0 group than the Pro0.6 and Pro1.0 groups. The crude protein digestibility was higher (p < 0.05) in the Pro0.6 group compared to the STD, STD0.6 and STD1.0 treatment groups while crude fat digestibility was higher (p < 0.05) in the STD and Pro0.6 compared with the STD0.6 and STD1.0 groups. Digestibility was higher for histidine (p < 0.05), leucine (p < 0.05) in the protease Pro0.6 and Pro1.0 groups than in the STD0.6 and STD1.0 groups. The digestibility of non-essential AA was higher for alanine (p < 0.05) in the Pro0.6 than the STD1.0 group. For faecal microbial population, Faecalibacterium abundance was higher (p < 0.05) in the Pro0.6 compared to all the other groups while the population of Actinobacteria was greater (p < 0.05) in the STD group and lowest in the Pro1.0 treatment. In the ileum, villus height was greater (p < 0.05) in the protease Pro0.6, and Pro1.0 groups compared to the STD0.6, and STD1.0 groups while the villus height to crypts depth ratio was lower (p < 0.05) in the STD 1.0 group compared to the STD, Pro0.6, and Pro1.0 groups. Based on these results, dietary protease supplementation improved nutrient digestibility and gut histo-morphology translating to improved utilisation of nutrients thus positively impacting growth performance in weaned pigs. Further, reducing the CP content in the diets increased the abundance of Muribaculaceae while protease supplementation increased the population of Faecalibacterium in the gut of the weanling piglets on the STD0.6 diet.

Effect of Visually Induced Motion Sickness from Head-Mounted Display on Cardiac Activity.

Head-mounted display (HMD) virtual reality devices can facilitate positive experiences such as co-presence and deep immersion; however, motion sickness (MS) due to these experiences hinders the development of the VR industry. This paper proposes a method for assessing MS caused by watching VR content on an HMD using cardiac features. Twenty-eight undergraduate volunteers participated in the experiment by watching VR content on a 2D screen and HMD for 12 min each, and their electrocardiogram signals were measured. Cardiac features were statistically analyzed using analysis of covariance (ANCOVA). The proposed model for classifying MS was implemented in various classifiers using significant cardiac features. The results of ANCOVA reveal a significant difference between 2D and VR viewing conditions, and the correlation coefficients between the subjective ratings and cardiac features have significant results in the range of -0.377 to -0.711 (for SDNN, pNN50, and ln HF) and 0.653 to 0.677 (for ln VLF and ln VLF/ln HF ratio). Among the MS classification models, the linear support vector machine achieves the highest average accuracy of 91.1% (10-fold cross validation) and has a significant permutation test outcome. The proposed method can contribute to quantifying MS and establishing viewer-friendly VR by determining its qualities.

Occurrence of metabolic diseases associated with antipsychotic use among Korean patients with schizophrenia.

OBJECTIVE: Metabolic side effects of antipsychotics significantly affect adherence to medication. We aimed to identify factors associated with the occurrence of metabolic diseases among Korean patients with schizophrenia (SCZ) from the national health insurance system database. We evaluated the frequency of antidiabetic and antihyperlipidemic use after diagnosis of SCZ according to typical or atypical antipsychotic use. MATERIALS AND METHODS: Among the 43,800 patients diagnosed with SCZ between 2008 and 2012, 29,591 patients who had no metabolic diseases before the diagnosis were included in the analysis to investigate the occurrence of metabolic diseases associated with antipsychotic use. The associations between the development of metabolic diseases and patient characteristics were evaluated using logistic regression analysis. RESULTS: Use of both typical and atypical antipsychotics (multivariate-adjusted odds ratio (OR), 1.2513; 95% confidence interval (CI), 1.0953 - 1.4294) was associated with higher incidence of metabolic diseases than without their use. Among the atypical antipsychotics, use of clozapine (multivariate-adjusted OR, 1.1959; 95% CI, 1.0086 - 1.4179) and quetiapine (multivariate-adjusted OR, 1.1284; 95% CI, 1.0446 - 1.2189) showed higher incidence of metabolic diseases compared to that without their use. Among the patients using ≥ 1 type of antidiabetic or antihyperlipidemic agents within 6 years after diagnosis of SCZ, the proportion of patients using only atypical antipsychotics was greater than those using only typical antipsychotics. CONCLUSION: The use of both typical and atypical antipsychotics, and clozapine and quetiapine treatment, may be associated with the occurrence of metabolic diseases in patients with SCZ. Additional prospective studies with accurate dosage information are needed to validate our findings.

Effects of Wearable Powered Exoskeletal Training on Functional Mobility, Physiological Health and Quality of Life in Non-ambulatory Spinal Cord Injury Patients.

BACKGROUND: Spinal cord injury (SCI) is a serious clinical condition that impacts a patient's physical, psychological, and socio-economic status. The aim of this pilot study was to evaluate the effects of training with a newly developed powered wearable exoskeleton (Hyundai Medical Exoskeleton [H-MEX]) on functional mobility, physiological health, and quality of life in non-ambulatory SCI patients. METHODS: Participants received 60 minutes of walking training with a powered exoskeleton 3 times per week for 10 weeks (total 30 sessions). The 6-minute walking test (6MWT) and timed-up-and-go test (TUGT) were performed to assess ambulatory function. The physiological outcomes of interest after exoskeleton-assisted walking training were spasticity, pulmonary function, bone mineral density, colon transit time, and serum inflammatory markers. Effects of walking training on subjective outcomes were estimated by the Korean version of the Falls Efficacy Scale-International and the 36-Item Short-Form Health Survey version 2. RESULTS: Ten participants finished 30 sessions of training and could ambulate independently. No severe adverse events were reported during the study. After training, the mean distance walked in the 6MWT (49.13 m) was significantly enhanced compared with baseline (20.65 m). The results of the TUGT also indicated a statistically significant improvement in the times required to stand up, walk 3 m and sit down. Although not statistically significant, clinically meaningful changes in some secondary physiological outcomes and/or quality of life were reported in some participants. CONCLUSION: In conclusion, this study demonstrated that the newly developed wearable exoskeleton, H-MEX is safe and feasible for non-ambulatory SCI patients, and may have potential to improve quality of life of patients by assisting bipedal ambulation. These results suggest that the H-MEX can be considered a beneficial device for chronic non-ambulatory SCI patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04055610.

Pharyngeal reflux episodes in patients with suspected laryngopharyngeal reflux versus healthy subjects: a prospective cohort study.

PURPOSE: This study aimed to analyze pharyngeal reflux episodes in patients with suspected LPR versus healthy subjects using 24-h MII-pH monitoring. METHODS: One hundred twenty-one patients who visited our clinic with a chief complaint of LPR-related symptoms and underwent 24-h MII-pH monitoring were enrolled prospectively. Also, 27 healthy subjects were enrolled and underwent 24-h MII-pH monitoring during the same period. We analyzed sensitivity, specificity, and accuracy comprehensively to determine appropriate cut-off values of pharyngeal reflux episodes in 24-h MII-pH monitoring to diagnose patients with LPR. RESULTS: Twenty-nine of 121 patients with suspected LPR showed no pharyngeal reflux episodes, while 92 showed more than one pharyngeal reflux event. In contrast, the 22 healthy subjects showed no pharyngeal reflux episodes, three showed one reflux event, and two showed two reflux events. A cut-off value of ≥ 1 showed best accuracy reflected by combined sensitivity and specificity values, while ≥ 2 demonstrated better specificity with slight loss of sensitivity and slightly lower overall accuracy, suggesting cut-off value of ≥ 1 pharyngeal reflux episodes is a good clinical indicator. CONCLUSION: A cut-off value of ≥ 1 in pharyngeal reflux episodes on 24-h MII-pH monitoring in patients with suspected LPR might be an acceptable diagnostic tool for LPR.

Non-Contact Measurement of Motion Sickness Using Pupillary Rhythms from an Infrared Camera.

Both physiological and neurological mechanisms are reflected in pupillary rhythms via neural pathways between the brain and pupil nerves. This study aims to interpret the phenomenon of motion sickness such as fatigue, anxiety, nausea and disorientation using these mechanisms and to develop an advanced non-contact measurement method from an infrared webcam. Twenty-four volunteers (12 females) experienced virtual reality content through both two-dimensional and head-mounted device interpretations. An irregular pattern of the pupillary rhythms, demonstrated by an increasing mean and standard deviation of pupil diameter and decreasing pupillary rhythm coherence ratio, was revealed after the participants experienced motion sickness. The motion sickness was induced while watching the head-mounted device as compared to the two-dimensional virtual reality, with the motion sickness strongly related to the visual information processing load. In addition, the proposed method was verified using a new experimental dataset for 23 participants (11 females), with a classification performance of 89.6% (n = 48) and 80.4% (n = 46) for training and test sets using a support vector machine with a radial basis function kernel, respectively. The proposed method was proven to be capable of quantitatively measuring and monitoring motion sickness in real-time in a simple, economical and contactless manner using an infrared camera.

A Hybrid Brain-Computer Interface for Real-Life Meal-Assist Robot Control.

Assistant devices such as meal-assist robots aid individuals with disabilities and support the elderly in performing daily activities. However, existing meal-assist robots are inconvenient to operate due to non-intuitive user interfaces, requiring additional time and effort. Thus, we developed a hybrid brain-computer interface-based meal-assist robot system following three features that can be measured using scalp electrodes for electroencephalography. The following three procedures comprise a single meal cycle. (1) Triple eye-blinks (EBs) from the prefrontal channel were treated as activation for initiating the cycle. (2) Steady-state visual evoked potentials (SSVEPs) from occipital channels were used to select the food per the user's intention. (3) Electromyograms (EMGs) were recorded from temporal channels as the users chewed the food to mark the end of a cycle and indicate readiness for starting the following meal. The accuracy, information transfer rate, and false positive rate during experiments on five subjects were as follows: accuracy (EBs/SSVEPs/EMGs) (%): (94.67/83.33/97.33); FPR (EBs/EMGs) (times/min): (0.11/0.08); ITR (SSVEPs) (bit/min): 20.41. These results revealed the feasibility of this assistive system. The proposed system allows users to eat on their own more naturally. Furthermore, it can increase the self-esteem of disabled and elderly peeople and enhance their quality of life.

Oral absorption of voriconazole is affected by SLCO2B1 c.*396T>C genetic polymorphism in CYP2C19 poor metabolizers.

High pharmacokinetic variability of voriconazole is mainly explained by CYP2C19 phenotype, but there are still unknown factors affecting the variability. In this study, the effect of solute carrier organic anion transporter family member 2B1 (SLCO2B1) genotype on the pharmacokinetics (PKs) of voriconazole was evaluated in 12 healthy CYP2C19 poor metabolizers after a single administration of voriconazole 200 mg intravenously and orally. In addition, the influence of CYP3A4 enzyme activity was also explored. The oral absorption of voriconazole was decreased and delayed in the subjects with the SLCO2B1 c.*396T>C variant compared to the subjects with wild type. However, the CYP3A activity markers measured in this study did not show significant association with metabolism of voriconazole. The results suggest that the SLCO2B1 c.*396T>C may be associated with the decreased function of intestinal OATP2B1, and it could contribute to interindividual PK variability of voriconazole.

URC102, a potent and selective inhibitor of hURAT1, reduced serum uric acid in healthy volunteers.

OBJECTIVE: URC102, a novel and potent inhibitor of human uric acid transporter 1 (hURAT1), is currently under clinical development to treat patients with gout. We performed a randomized, double-blind, placebo-controlled, phase I study to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of URC102 after single and multiple oral administration in healthy male subjects. METHODS: Thirty-one Koreans and 23 Caucasians received a single dose of URC102 at 1-30 mg and 1-10 mg, respectively, while 44 Koreans received URC102 once-daily for 7 days at 1-20 mg. We evaluated safety and tolerability throughout the study, and serially determined serum uric acid, the fractional excretion of uric acid and URC102 concentrations. RESULTS: URC102 was well tolerated over the dose range of 1-10 mg after single and multiple administration. URC102 rapidly reduced serum uric acid, which was maintained over the entire treatment period. Furthermore, URC102 increased the area-under-the-effect curve over 168 h for fractional excretion of uric acid in a dose-dependent manner. The maximum plasma concentration and the area under the plasma concentration-time curve of URC102 increased dose-proportionally. The pharmacokinetic and pharmacodynamics characteristics of URC102 were similar in Koreans and Caucasians. CONCLUSION: URC102 was safe and effectively lowered serum uric acid, which should be tested and confirmed in patients with hyperuricaemia and/or gout through further studies. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01953497 and NCT02524678.

The effect of carbon nanotube chirality on the electrical conductivity of polymer nanocomposites considering tunneling resistance.

In this study, the effect on the conductance of polymer nanocomposites considering quantum tunneling resistance is investigated with respect to the chirality of carbon nanotubes (CNTs) and uncertainties in the geometric parameters of CNTs by using Monte Carlo simulations. The random spatial placement for CNTs was accomplished with a one-dimensional line segment and the periodic boundary conditions were applied to CNTs in the two-dimensional representative volume element. Intersection points between each CNT were calculated to obtain connectivity lists of the connected network path. Both the intrinsic resistance of the CNT and the inter-CNT tunneling resistance were considered in this model. In addition, the in-house code developed was validated by comparison with several experimental datasets from the literature. Unlike past studies, uncertainties in the chiral index of single-wall CNTs concerning armchair and zig-zag structures have been considered here and the electrical conductivity and percolation threshold are predicted.

Pharmacokinetic comparison of gemigliptin 50 mg and metformin 500 mg as a fixed-dose combination and loose combination
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BACKGROUND: Metformin and dipeptidyl peptidase-4 (DPP-IV) inhibitors are commonly combined to treat patients with diabetes mellitus (DM). A new fixed-dose combination (FDC) drug containing gemigliptin, a DPP-IV inhibitor, and sustained-release metformin has been developed. This study aimed to compare the PKs and tolerability of FDC versus loose combination of gemigliptin 50 mg and metformin 500 mg. MATERIALS AND METHODS: A randomized, open-label, two-treatment, two-period, two-sequence, crossover study was conducted in 28 healthy subjects, who received a single oral dose of an FDC tablet of gemigliptin (50 mg) and sustained-release metformin (500 mg) or were coadministered gemigliptin (50 mg) and extended-release metformin (500 mg) with a 1-week washout. Serial blood samples were collected up to 48 hours after study drug administration, and the plasma concentrations of gemigliptin, LC15-0636 (active metabolite of gemigliptin), and metformin were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using a noncompartmental method. Safety and tolerability were evaluated based on vital signs, adverse events, clinical laboratory tests, and electrocardiography. RESULTS: The concentration-time profiles of gemigliptin and metformin were similar when they were administered as FDC or were coadministered. The geometric mean ratio (GMR) and its 90% CIs of Cmax for gemigliptin, LC15-0636, and metformin were 0.93 (0.85 - 1.02), 1.00 (0.94 - 1.06), and 1.03 (0.98 - 1.09), respectively. The corresponding values of AUClast were 0.97 (0.93 - 1.01), 1.00 (0.97 - 1.04), and 1.00 (0.95 - 1.05), respectively. There were no clinically meaningful differences in safety and tolerability. CONCLUSION: When comparing the AUClast and Cmax of gemigliptin, LC15-0636, and metformin, the 90% CIs were all within the range of 0.8 - 1.25, which is the commonly accepted range for evaluating bioequivalence.

IR-camera-based measurements of 2D/3D cognitive fatigue in 2D/3D display system using task-evoked pupillary response.

This study was carried out to evaluate a method used to measure three-dimensional (3D) cognitive fatigue based on the pupillary response. This technique was designed to overcome measurement burdens by using non-contact methods. The pupillary response is related to cognitive function by a neural pathway and may be an indicator of 3D cognitive fatigue. Twenty-six undergraduate students (including 14 women) watched both 2D and 3D versions of a video for 70 min. The participants experienced visual fatigue after viewing the 3D content. Measures such as subjective rating, response time, event-related potential latency, heartbeat-evoked potential (HEP) alpha power, and task-evoked pupillary response (TEPR) latency were significantly different. Multitrait-multimethod matrix analysis indicated that HEP and TEPR latency measures had stronger reliability and higher correlations with 3D cognitive fatigue than other measures. TEPR latency may be useful for quantitatively determining 3D visual fatigue, as it can be easily used to evaluate 3D visual fatigue using a non-contact method without measuring burden.

The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension.

The metabolism of posaconazole is mediated mainly by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, especially UGT1A4. The aim of this study was to investigate the effects of genetic polymorphisms on the posaconazole plasma concentration (PPC). This prospective study was conducted from September 2014 to August 2016. We enrolled patients with acute myeloid leukemia or myelodysplastic syndrome treated with posaconazole oral suspension (200 mg) three times daily for fungal prophylaxis. The patients were examined for the multidrug resistance gene 1 3435C>T and 2677G>T/A variations and the UGT1A4*3 allele by direct sequencing of DNA from peripheral whole-blood samples. We defined poor absorbers to be those with PPCs of <200 ng/ml and the optimal PPC to be ≥700 ng/ml on day 8. The associations between genetic polymorphisms and the PPC were evaluated using multivariate logistic regression analysis including clinical variables. During the study period, 132 patients were enrolled. Six patients (4.5%) were defined as poor absorbers, and 49 patients (37.1%) did not reach the optimal PPC on day 8. In multivariate analysis, the independent risk factors for a poor absorber were at least one UGT1A4*3 allele (adjusted odds ratio [aOR], 18.81; 95% confidence interval [CI], 1.09 to 324.44; P = 0.043) and poor oral food intake (aOR per -100 kcal, 1.44; 95% CI, 1.04 to 1.99; P = 0.029). There was no statistically significant association between the genetic polymorphisms and achievement of the optimal PPC on day 8. The UGT1A4*3 polymorphism is an independent risk factor for being a poor absorber of posaconazole oral suspension in patients with hematological malignancies.

Early Therapeutic Drug Monitoring of Posaconazole Oral Suspension in Patients With Hematologic Malignancies.

BACKGROUND: Therapeutic drug monitoring (TDM) of posaconazole is usually performed 1 week after starting the drug because of its long half-life. However, previous studies showed that measuring the posaconazole plasma concentration (PPC) on day 3 is effective for predicting steady-state levels. The purpose of this study was to evaluate the relevance of early TDM (day 3) of posaconazole for achieving an optimal PPC. METHODS: This prospective study was conducted from September 2014 to August 2016. A total of 148 patients with acute myeloid leukemia or myelodysplastic syndromes received a 200 mg posaconazole oral suspension 3 times daily for fungal prophylaxis. During the period from September 2014 to December 2015 (control group), no dose adjustment was performed on day 3. During the period from January 2016 to Aug 2016 (early TDM group), the frequency of posaconazole 200-mg administration was increased to 4 times daily in patients whose PPC on day 3 was <400 ng/mL. The cutoff value for optimal PPC on day 8 was defined as 500 ng/mL. RESULTS: In 21 of 107 patients (20%) in the control group, PPC was <400 ng/mL on day 3. In 15 (71%) of these 21 patients, the PPC was suboptimal on day 8. In the early TDM group, the PPC was <400 ng/mL on day 3 in 4 of 41 patients (10%). After increasing the posaconazole administration frequency in these 4 patients, PPC was suboptimal on day 8 in 1 patient (25%). In both groups, 104 patients had a PPC of ≥500 ng/mL on day 3, but 7% (7/104) of these had a suboptimal level on day 8. CONCLUSIONS: Early TDM on day 3 for posaconazole suspension may help more patients achieve optimal drug levels on day 8, although TDM on day 8 is needed even in patients with optimal levels on day 3.

Bioequivalence assessment of tulobuterol transdermal delivery system in healthy subjects
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OBJECTIVE: The purpose of this study was to evaluate the bioequivalence in the pharmacokinetics of two 2-mg tulobuterol transdermal delivery systems (TDSs) in healthy subjects. MATERIALS AND METHODS: The pharmacokinetic (PK) analysis was performed using data from a randomized, open-label, single-dose, two-way, two-period, crossover study. Eligible subjects received either the Bretol®patch (test drug) or Hokunalin®patch (reference drug) in sequence according to their allocated group. Serial blood samples for PK analyses were collected for up to 48 hours after tulobuterol TDS application. The PK parameters, including the maximum concentration (Cmax) and area under the curve from time zero to the last quantifiable concentration time (AUClast), were estimated by using noncompartmental analysis. The geometric mean ratios (GMRs) of the Cmax and AUClast and their 90% confidence intervals (CIs) were estimated. RESULTS: A total of 27 subjects completed the study as planned. The concentration-time profiles of tulobuterol were similar in both formulations. The GMRs (90% CIs) of Cmax and AUClast were 0.9443 (0.8790 - 1.0144) and 0.9600 (0.8660 - 1.0642), respectively. CONCLUSION: The PK profiles of both tulobuterol TDSs were comparable. In addition, the 90% CIs of the GMR were within the bioequivalence criteria of 0.800 - 1.250. Therefore, the Bretol®patch can be used as an alternative to the Hokunalin®patch for the treatment of patients with asthma and chronic obstructive pulmonary disease.
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