Factors Influencing Serum Posaconazole Concentrations in Patients with Hematologic Malignancies Receiving Delayed-Release Tablets.

BACKGROUND: Posaconazole (PCZ) plays a crucial role in the prophylaxis and treatment of invasive fungal infections in hematologic malignancies. PCZ concentrations reportedly vary among patients receiving delayed-release tablets (DRT). However, the factors influencing these concentrations remain insufficiently elucidated. Therefore, this study aimed to evaluate the factors influencing PCZ concentrations and their effect on the probability of target attainment (PTA) using a population pharmacokinetic (PPK) approach. We also explored the relationship between PCZ exposure and hepatotoxicity. METHODS: This retrospective study included adult patients with hematologic malignancies who received PCZ DRT. A PPK model was developed based on observational data for 130 concentrations in 28 patients. Simulation analyses were performed to assess the PTA at standard doses of 0.7 and 1.0 mg/L for prophylaxis and treatment, respectively. Estimated concentrations were used to evaluate the correlation between PCZ exposure and hepatotoxicity. RESULTS: Significant factors influencing PCZ concentrations included body weight, serum total protein levels, and diarrhea. Diarrhea correlated with decreased PCZ concentrations resulting in up to 26% lower PTA compared with that without diarrhea. Moreover, PTA declined markedly as the total protein levels decreased from 6.6 g/dL to 4.4 g/dL. The incidence of hepatotoxicity was 17.4% (4/23); no significant relationship could be established between the PCZ concentrations and hepatotoxicity (P = 0.188). CONCLUSIONS: We identified the factors affecting PCZ exposure, which could not be detected by PPK analysis using data from clinical trials. Our results suggest that the generally recommended dose of PCZ causes underexposure in patients with hematologic malignancies characterized by high body weight, hypoproteinemia, or concurrent diarrhea. Therapeutic drug monitoring for DRT may be recommended, especially in patients with these risk factors.

Risk Factors of Cetuximab-Induced Hypomagnesemia and the Effect of Magnesium Prophylaxis in Patients with Head and Neck Cancer: A Retrospective Study.

Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78-20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52-19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.

Population Pharmacokinetic Analysis of Drug-Drug Interactions Between Perampanel and Carbamazepine Using Enzyme Induction Model in Epileptic Patients.

BACKGROUND: Perampanel (PER) is an oral antiepileptic drug and its concomitant use with carbamazepine (CBZ) leads to decreased PER concentrations. However, the magnitude of its influence may vary, depending on the dynamics of the enzyme induction properties of CBZ. This study aimed to develop a population pharmacokinetic (PPK) model considering the dynamics of enzyme induction and evaluate the effect of CBZ on PER pharmacokinetics. METHODS: We retrospectively collected data on patient background, laboratory tests, and prescribed drugs from electronic medical records. We developed 2 PPK models incorporating the effect of CBZ-mediated enzyme induction to describe time-concentration profiles of PER using the following different approaches: (1) treating the concomitant use of CBZ as a categorical covariate (empirical PPK model) and (2) incorporating the time-course of changes in the amount of enzyme by CBZ-mediated induction (semimechanistic PPK model). The bias and precision of the predictions were investigated by calculating the mean error, mean absolute error, and root mean squared error. RESULTS: A total of 133 PER concentrations from 64 patients were available for PPK modelling. PPK analyses showed that the co-administration of CBZ increased the clearance of PER. Goodness-of-fit plots indicated a favorable description of the observed data and low bias. The mean error, mean absolute error, and root mean square error values based on the semimechanistic model were smaller than those obtained using the empirical PPK model for predicting PER concentrations in patients with CBZ. CONCLUSIONS: We developed 2 PPK models to describe PER pharmacokinetics based on different approaches, using electronic medical record data. Our PPK models support the use of PER in clinical practice.

Population pharmacokinetic model and dosing optimization of vancomycin in hematologic malignancies with neutropenia and augmented renal clearance.

AIM: Data on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies. METHODS: A retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC0-24 of 400-600 mg h/L at the steady-state. RESULTS: The VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients. CONCLUSION: AML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended.

Systematic surveillance of immune-related adverse events in clinical practice and impact of subsequent steroid medication on survival outcomes.

BACKGROUND: Recent advances in immune-checkpoint inhibitors (ICIs) have highlighted the need for effective management of immune-related adverse events (irAEs). This study aimed to conduct a systematic surveillance of real-world development of irAEs for understanding their characteristics and examine the prognostic impact of steroid use for these events. METHODS: We retrospectively investigated cancer patients treated with ICIs between 2014 and 2021 and collected information about irAEs throughout their development, management, and clinical outcomes. RESULTS: Overall, 458 patients (45.4%) developed 670 irAEs. The prevalence of irAEs varied by cancer type, but it was increased in regimens with longer treatment durations. Severe irAEs were more common in the nivolumab + ipilimumab and pembrolizumab + axitinib regimens. Patients who received steroids for irAEs at a dosage of < 2 mg/kg had comparable prognosis to those who did not receive steroids; however, patients who received methylprednisolone pulse therapy, primarily for severe pneumonitis and hepatitis, had shorter overall survival than those who did not receive steroids (7.8 versus 23.4 months, p = 0.016). Furthermore, methylprednisolone pulse therapy for irAEs was a poor prognostic factor in multivariate analysis (hazard ratio: 2.19, 95% confidence interval: 1.34-2.86, p < 0.001). CONCLUSION: Steroid treatment for irAE does not affect prognosis and should thus be used promptly to control inflammation. However, pulse therapy for severe cases is a poor prognostic factor, and early detection remains the key to managing such irAEs. The irAE characteristics in each regimen should be clarified to establish and provide more sophisticated irAE management, and the current findings will be beneficial to this goal.

Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients With FLT3 Mutation-Positive Acute Myelogenous Leukemia.

BACKGROUND: Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography-tandem mass spectrometry. METHODS: Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 µm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode. RESULTS: The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10-1000 ng/mL, r 2 > 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias -4.2% to 1.9%), precision (intraday CV ≤ 7.9%; interday CV ≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML. CONCLUSIONS: The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.

Risk Factors for Gemcitabine-Induced Vascular Pain in Patients With Pancreatic Cancer.

BACKGROUND: Peripheral intravenous injection of gemcitabine often causes vascular pain; however, preventive measures have not yet been established. OBJECTIVES: This study focused on identifying predictive factors for gemcitabine-induced vascular pain. METHODS: We retrospectively analyzed risk factors for developing vascular pain in patients with pancreatic cancer receiving gemcitabine infusions at our institution. Infusions were divided into groups according to presence or absence of vascular pain symptoms, and variables were compared. Odds ratios for risk factors were calculated using logistic regression analyses. RESULTS: Overall, 272 patients with pancreatic cancer were subjected to 725 gemcitabine infusions, and of these, 18.4% (n = 50) experienced vascular pain. There were significant differences in the gemcitabine dose (P = 0.025), dose of gemcitabine/body surface area (BSA; P = 0.004), concentration of gemcitabine (P = 0.025), and hot pack use (P = 0.011) between the vascular pain and no vascular pain groups. Multivariable analyses indicated that gemcitabine dose/BSA and lack of hot pack use were risk factors for developing vascular pain. Moreover, on administration of a higher dosage (>930 mg/m2), the incidence of vascular pain in patients using a hot pack (6.7%) was significantly lower than that in patients not provided a hot pack (16.2%). CONCLUSIONS AND RELEVANCE: High gemcitabine dosages and lack of hot pack use were predictive factors for gemcitabine-induced vascular pain in patients with pancreatic cancer. Patients receiving gemcitabine treatment should apply a hot pack to the injection site. Scrupulous clinical attention is required for patients presenting with these risk factors to improve pain management.

Development and Full Validation of a Bioanalytical Method for Quantifying Letermovir in Human Plasma Using Ultra-Performance Liquid Chromatography Coupled with Mass Spectrometry.

With the aim of studying the pharmacokinetics of letermovir, which is a newly developed antiviral agent for human cytomegalovirus, a rapid and simple ultra-performance liquid chromatography coupled with mass spectrometry (UPLC/MS) method was developed and validated for the quantification of letermovir in human plasma. Separation was performed in reverse phase mode using an ACQUITY UPLC BEH C18 column (130 Å, 1.7 µm, 2.1 × 50 mm) at a flow rate of 0.3 mL/min, 10 mM ammonium acetate-0.1% formic acid solution as mobile phase A, and acetonitrile as mobile phase B with a gradient elution. The method was validated over a linear range of 10-1000 ng/mL with a coefficient of determination (R2) >0.99 using weighted linear regression analysis. The intra- and inter-assay accuracy (nominal%) and precision (relative standard deviation%) were within ±15 and ≤15%, respectively. The specificity, recovery, matrix effect, stability, and dilution integrity of this method were also within acceptable limits. This method could be useful in studying the pharmacokinetics and pharmacodynamics, as well as performing the therapeutic drug monitoring of letermovir.

Comparison of 4 Commercial Immunoassays Used in Measuring the Concentration of Tacrolimus in Blood and Their Cross-Reactivity to Its Metabolites.

BACKGROUND: Therapeutic drug monitoring of tacrolimus is necessary for appropriate dose adjustment for a successful immunosuppressive therapy. Several commercial immunoassays are available for tacrolimus measurements. This study aimed at simultaneously evaluating the analytical performances of 4 such immunoassays, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a standard. For the first time, cross-reactivity to tacrolimus metabolites was assessed at concentrations frequently observed in clinical settings, as opposed to the higher concentrations tested by assay manufacturers. METHODS: An affinity column-mediated immunoassay (ACMIA), using upgraded flex reagents; released in 2015, a chemiluminescence immunoassay (CLIA), an electrochemiluminescence immunoassay (ECLIA), and a latex agglutination turbidimetric immunoassay (LTIA) were evaluated using frozen whole blood samples collected from transplantation patients. Cross-reactivities to 3 major tacrolimus metabolites (13-O-demethyl-tacrolimus [M-I], 31-O-demethyl-tacrolimus [M-II], and 15-O-demethyl-tacrolimus [M-III]) were evaluated. RESULTS: Each immunoassay correlated well with LC-MS/MS, and the Pearson's correlation coefficients (R) were 0.974, 0.977, 0.978, and 0.902 for ACMIA, CLIA, ECLIA, and LTIA, respectively. Using Bland-Altman difference plots to compare the immunoassays with LC-MS/MS, the calculated average biases were -6.73%, 6.07%, 7.46%, and 12.27% for ACMIA, CLIA, ECLIA, and LTIA, respectively. The cross-reactivities of ACMIA to the tacrolimus metabolites M-II and M-III were 81% and 78%, respectively, when blood was spiked at 2 ng/mL, and 94% and 68%, respectively, when it was spiked at 5 ng/mL. CONCLUSIONS: Each immunoassay was useful, but had its own characteristics. ACMIA cross-reactivities to M-II and M-III were much higher than the respective 18% and 15% reported on its package insert, suggesting that cross-reactivity should be examined at clinically relevant concentrations.

Effects of Concomitant Administration of Vonoprazan Fumarate on the Tacrolimus Blood Concentration in Kidney Transplant Recipients.

Vonoprazan fumarate (vonoprazan) is a new kind of acid suppressant with potent acid inhibitory effects. Therefore, it has been administered to kidney transplant recipients for treatment or prophylaxis of steroid ulcers, refractory peptic ulcers, and gastroesophageal reflux disease. Because tacrolimus, which is a well-established immunosuppressant for kidney transplantation, and vonoprazan share the CYP3A4 system for metabolism, drug interactions are anticipated upon simultaneous administration. We retrospectively analyzed 52 kidney transplant recipients who were converted from rabeprazole, which has a small effect on the tacrolimus trough blood concentration (C0), to vonoprazan between August 2016 and July 2019. We compared the tacrolimus C0/tacrolimus dose (C0/D) before and after conversion and serum liver enzymes, serum total bilirubin, and the estimated glomerular filtration rate (eGFR). As a result, mean tacrolimus C0/D before and after conversion was 1.98 ± 1.02 and 2.19 ± 1.15 (ng/mL)/(mg/d), respectively, (p < 0.001). Additionally, mean aspartate transaminase (AST) before and after conversion was 18.6 ± 4.2 and 19.6 ± 5.2 IU/L, respectively, (p = 0.037). Mean alanine transaminase (ALT) before and after conversion was 15.8 ± 5.5 and 17.6 ± 7.1 IU/L, respectively, (p = 0.007). Mean eGFR before and after conversion was 50.6 ± 14.4 and 51.4 ± 14.7 mL/min/1.73 m2, respectively (p = 0.021). Mean AST, ALT, and eGFR were slightly but significantly elevated within normal ranges after conversion. In conclusion, our study suggests that the mean tacrolimus C0/D was elevated significantly by converting from rabeprazole to vonoprazan, but it had little clinical significance. Vonoprazan can be administered safely to kidney transplant recipients receiving tacrolimus.

Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation.

It is well known that the CYP3A5*3 polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether POR*28 as well as CYP3A5*3 polymorphism in Japanese recipients and donors would be another biomarker for the variation of tacrolimus blood levels in the recipients during the first month after living-donor liver transplantation. We enrolled 65 patients treated with tacrolimus, who underwent liver transplantation between July 2016 and January 2019. Genomic DNA was extracted from whole-blood samples, and genotyping was performed to examine the presence of CYP3A5*3 and POR*28 polymorphisms in the recipients and donors. The CYP3A5*3/*3 genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of CYP3A5 expressor vs. CYP3A5 non-expressor, p value]: Pod 1-7, ß= -0.389 [1.76 vs. 2.73, p < 0.001]; Pod 8-14, ß = -0.345 [2.03 vs. 2.83, p < 0.001]; Pod 15-21, ß= -0.417 [1.75 vs. 2.94, p < 0.001]; Pod 22-28, ß = -0.627 [1.55 vs. 2.90, p < 0.001]) rather than donor (Pod 1-7, ß = n/a [1.88 vs. 2.76]; Pod 8-14, ß = n/a [1.99 vs. 2.93]; Pod 15-21, ß = -0.175 [1.91 vs. 2.94, p = 0.004]; Pod 22-28, ß = n/a [1.61 vs. 2.67]) significantly contributed to the increase in the concentration/dose (C/D) ratio of tacrolimus for at least one month after surgery. We found that the tacrolimus C/D ratio significantly decreased from the third week after transplantation when the recipient carried both CYP3A5*1 (functional CYP3A5) and POR*28 (n = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39-2.17]), compared with that in the recipients carrying CYP3A5*1 and POR*1/*1 (n = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05-3.06]) (p < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the POR*28 polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying CYP3A5*1 rather than CYP3A5*3/*3.

Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation.

Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.

Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation.

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2-3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.

Neutrophil Gelatinase-Associated Lipocalin Is Not Associated with Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients Who Received Mycophenolate Mofetil with Delayed Introduction of Tacrolimus.

Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication. The urinary neutrophil gelatinase-associated lipocalin (NGAL) level has been linked to tacrolimus-induced AKI in patients starting tacrolimus treatment the morning after liver transplantation. Here we tested this association using a different immunosuppression protocol: Mycophenolate mofetil administration beginning on Postoperative Day 1 and tacrolimus administration beginning on Postoperative Day 2 or 3. Urine samples were collected from 26 living donor liver transplant recipients before (Postoperative Day 1) and after (Postoperative Day 7 or 14) tacrolimus administration. NGAL levels were measured via enzyme-linked immunosorbent assays, as were those of three additional urinary biomarkers for kidney diseases: Monocyte chemotactic protein-1 (MCP-1), liver-type fatty acid-binding protein (L-FABP), and human epididymis secretory protein 4 (HE4). HE4 levels after tacrolimus administration were significantly higher in patients who developed AKI (n = 6) than in those who did not (n = 20), whereas NGAL, MCP-1, and L-FABP levels did not differ significantly before or after tacrolimus administration. These findings indicate that NGAL may not be a universal biomarker of AKI in tacrolimus-treated liver transplant recipients. To reduce the likelihood of tacrolimus-induced AKI, our immunosuppression protocol is recommended.

Risk Factors for Predicting Severe Neutropenia Induced by Pemetrexed Plus Carboplatin Therapy in Patients with Advanced Non-small Cell Lung Cancer.

Pemetrexed plus carboplatin therapy is widely administered to patients with non-squamous non-small cell lung cancer. Although severe neutropenia is often observed during this combination therapy, its predictive factors are unknown. Therefore, we investigated the predictive factors for severe neutropenia in 77 patients treated with this combination therapy at the Department of Respiratory Medicine, Kyushu University Hospital, between September 2009 and September 2013. All data were retrospectively collected from the electronic medical record system, and univariate and multivariate logistic regression analyses were performed to identify risk factors for grade 3 or 4 neutropenia. Among the 77 patients, 34 (44%) developed grade 3 or 4 neutropenia. Multivariate analysis revealed that lower baseline hemoglobin values (odds ratio [OR], 1.97 per 1 g/dL decrease; 95% confidence interval [CI], 1.39-2.99, p<0.01) and lower baseline neutrophil counts (OR, 1.71 per 1000/mm(3) decrease; 95% CI, 1.14-2.71, p=0.01) were significantly associated with grade 3 or 4 neutropenia. During 4 courses of pemetrexed plus carboplatin therapy, the incidence of grade 3 or 4 neutropenia in patients with baseline hemoglobin values of <11.6 g/dL was significantly higher than that in patients with values of ≥11.6 g/dL [84% (16/19) vs. 31% (18/58), p<0.001]. In conclusion, patients with lower baseline neutrophil counts or lower baseline hemoglobin values, especially those with baseline hemoglobin values of <11.6 g/dL, should be monitored more carefully during pemetrexed plus carboplatin therapy.

Eye-tracking-based analysis of pharmacists' thought processes in the dispensing work: research related to the efficiency in dispensing based on right-brain thinking.

BACKGROUND: Pharmacists should be aware of their thought processes in dispensing work, including differences in the dispensing complexities owing to different drug positions in the left, center, and right areas. Dispensing errors associated with "same-name drugs (a pair of drugs with the same name but a different ingredient quantity)" are prevalent and often negatively affect patients. In this study, using five pairs of comparative models, the gaze movements of pharmacists in dispensing work were analyzed using an eye-tracking method to elucidate their thought processes. METHODS: We prepared verification slides and displayed them on a prescription monitor and three drug rack monitors. The dispensing information (drug name, drug usage, location display, and total amount) was displayed on a prescription monitor. A total of 180 drugs including five target drugs were displayed on the three drug rack monitors. Total gaze points in the prescription area, those in the drug rack area, total vertical movements between the two areas, and time required to dispense drugs were measured as the four classifications Gaze 1, Gaze 2, Passage, and Time, respectively. First, we defined the two types of location displays as "numeral combination" and "color/symbol combination." Next, we defined two pairs of models A1-A2 (numerals) and B1-B2 (color/symbol) to compare differences between the left and right areas. Moreover, three pairs of models C1-C2 (left), D1-D2 (center), and E1-E2 (right) were established to compare differences between "numeral combination" and "color/symbol combination." RESULTS: Significant differences in the complexities of dispensing work were observed in Gaze 2, Passage, and Time between the models A1-A2 (A1B2), and in Gaze 2 and Time between the models C1-C2, D1-D2, and E1-E2 (C1>C2, D1>D2, and E1>E2, respectively). CONCLUSIONS: Using the current dispensing rules, pharmacists are not good at dispensing drugs located in the right area. An effective measure for reducing the dispensing complexity is to introduce visual information in the prescription content; the utilization of the right brain facilitates reducing the complexity in the right dispensing area.

Decrease in venous irritation by adjusting the concentration of injected bendamustine.

Intravenous injection of bendamustine often causes venous irritation and also deteriorates the patient's quality of life. Thus, we evaluated the risk factors associated with venous irritation induced by bendamustine in patients with follicular lymphoma or mantle cell lymphoma. We also evaluated the effectiveness of intervention of changing the preparation procedure for bendamustine. All data were retrospectively collected from the electronic medical record system. In the initial analysis of the total 43 courses of bendamustine therapy, most patients (88%) were administered bendamustine with 250 mL of diluent according to the bendamustine package insert in Japan. The median concentration of bendamustine solution (0.56 mg/mL vs. 0.24 mg/mL) and the incidences of venous irritation (66% vs. 0%, p=0.01) were significantly different between the patients receiving bendamustine at 250 mL and 500 mL of diluent. Based on this result, we proposed changing the final volume of bendamustine dissolution from 250 to 500 mL, which is recommended in other countries. After this intervention, the incidence of venous irritation was significantly reduced from 58 to 20% (p=0.02). The incidence of venous irritation increased in a concentration-dependent manner (≤0.40 mg/mL: 6%; 0.41-0.60 mg/mL: 62%, p<0.001; >0.60 mg/mL: 75%, p<0.001). We conclude that a high concentration bendamustine solution is a risk factor for venous irritation and that 500 mL of diluent is ideal. To further reduce the incidence of venous irritation, the concentration of bendamustine solution is recommended to be 0.40 mg/mL or less.

Effectiveness and safety of antiemetic aprepitant in Japanese patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation.

For patients receiving high-dose chemotherapy, a 5-hydroxytryptamine 3 receptor antagonist combined with dexamethasone is a standard antiemetic therapy. Despite this prophylactic anti-emetic treatment, many patients still suffer from uncontrollable emesis. In this study, we retrospectively evaluated the antiemetic effectiveness and safety of aprepitant (a neurokinin-1 receptor antagonist) in addition to 5-HT3 antagonist in Japanese patients with hematologic malignancy receiving high-dose chemotherapy prior to autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-six patients received aprepitant and granisetron (the aprepitant group), whereas, 22 patients received granisetron alone (the control group). All patients received 3 mg of granisetron intravenously 30 min before chemotherapy administration. Patients in the aprepitant group additionally received 125 mg of aprepitant 60-90 min before administration of the first moderately to highly emetogenic chemotherapy. On the next day or thereafter, 80 mg of aprepitant was administered in the morning until the last administration of moderately to highly emetogenic anticancer drugs. The percentage of patients who achieved complete response (CR), defined as no emesis with only grade 1-2 nausea, in the aprepitant group was significantly higher than that in the control group (42% vs. 5%, p=0.003). Logistic regression analysis showed that non-prophylactic use of aprepitant was significantly associated with non-CR. The frequencies of adverse drug events (ADEs) were not significantly different between two groups. In conclusion, the results of this study suggest that the addition of aprepitant to granisetron can improve the antiemetic effect without increasing ADEs in patients receiving high-dose chemotherapy prior to auto-PBSCT.

Risk factors for predicting severe neutropenia induced by amrubicin in patients with advanced lung cancer.

BACKGROUND: Neutropenia is one of the most frequent and dose-limiting toxicities in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. METHODS: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3-4 neutropenia. RESULTS: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m(2). The incidence of grade 3-4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01-134.15; p = 0.049), higher AMR doses (40 mg/m(2) or more) (OR = 5.98; 95% CI 1.77-23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04-4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. CONCLUSION: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.

Clinical Pharmacokinetics and Pharmacodynamics of Fostamatinib and Its Active Moiety R406.

Fostamatinib is the first approved spleen tyrosine kinase inhibitor for chronic immune thrombocytopenia. This review summarizes the clinical development, pharmacokinetics, pharmacodynamics, drug-drug interactions, adverse events, and comprehensive analyses of fostamatinib. While integrating these findings, we discuss the fostering and improvement of fostamatinib for further clinical applications. Fostamatinib is designed as a prodrug and cleavage of its active moiety R406 in the intestine. As R406 is the major product in the blood, this review mainly discusses the pharmacokinetics and pharmacodynamics of R406. It is metabolized by cytochrome 3A4 and UGT1A9 in the liver and is dominantly excreted in feces after anaerobic modification by the gut microbiota. As fostamatinib and R406 strongly inhibit the breast cancer resistance protein, the interaction with those substrates, particularly statins, should be carefully monitored. In patients with immune thrombocytopenia, fostamatinib administration started at 100 mg twice daily, and most patients increased to 150 mg twice daily in the clinical trial. Although responders showed a higher R406 concentration than non-responders, the correlation between R406 exposure and achievement of the platelet count as a pharmacodynamic marker was uncertain in the pharmacokinetic/pharmacodynamic analysis. Additionally, R406 concentration was almost halved in patients with a heavy body weight; hence, the exposure-efficacy study for suitable dosing should be continued with post-marketing data. In contrast, the pharmacokinetic/pharmacodynamic analysis for exposure safety revealed that R406 exposure significantly correlated with the incidence of hypertension. Even though the influence of elevated exposure on other toxicities, including diarrhea and neutropenia, is still unclear, careful management is required with dose escalation to avoid toxicity-related discontinuation.