Development of a model to predict vancomycin serum concentration during continuous infusion of vancomycin in critically ill pediatric patients.

Vancomycin is a frequently used antibiotic in intensive care units, and the patient's renal clearance affects the pharmacokinetic characteristics of vancomycin. Several advantages have been reported for vancomycin continuous intravenous infusion, but studies on continuous dosing regimens based on patients' renal clearance are insufficient. The aim of this study was to develop a vancomycin serum concentration prediction model by factoring in a patient's renal clearance. Children admitted to our institution between July 1, 2021, and July 31, 2022 with records of continuous infusion of vancomycin were included in the study. Sex, age, height, weight, vancomycin dose by weight, interval from the start of vancomycin administration to the time of therapeutic drug monitoring sampling, and vancomycin serum concentrations were analyzed with the linear regression analysis of the mixed effect model. Univariable regression analysis was performed using the vancomycin serum concentration as a dependent variable. It showed that vancomycin dose (p < 0.001) and serum creatinine (p = 0.007) were factors that had the most impact on vancomycin serum concentration. Vancomycin serum concentration was affected by vancomycin dose (p < 0.001) and serum creatinine (p = 0.001) with statistical significance, and a multivariable regression model was obtained as follows: Vancomycin serum concentration (mg/l) = -1.296 + 0.281 × vancomycin dose (mg/kg) + 20.458 × serum creatinine (mg/dl) (adjusted coefficient of determination, R2 = 0.66). This prediction model is expected to contribute to establishing an optimal continuous infusion regimen for vancomycin.

Consultation-Based Deprescribing Service to Optimize Palliative Care for Terminal Cancer Patients.

(1) Background: A pharmacist-led deprescribing service previously developed within the Consultation-Based Palliative Care Team (CB-PCT) was implemented for terminal cancer patients. (2) Objective: To evaluate the clinical outcomes of the developed deprescribing service for terminal cancer patients in CB-PCT. (3) Methods: A retrospective analysis compared the active care (AC) group to the historical usual care (UC) group. The clinical outcomes included the deprescribing rate of preventive medications, the proportion of patients with one or more medication-related problems (MRPs) resolved upon discharge, and the clinical significance. The implementability of the service was also gauged by the acceptance rates of pharmacists' interventions. (4) Results: Preventive medications included lipid-lowering agents, gastroprotective agents, vitamins, antihypertensives, and antidiabetic agents. The AC group revealed a higher deprescribing rate (10.4% in the UC group vs. 29.6% in the AC group, p < 0.001). At discharge, more AC patients had one or more MRPs deprescribed (39.7% vs. 2.97% in UC, p < 0.001). The clinical significance consistently had a very significant rating (mean score of 2.96 out of 4). Acceptance rates were notably higher in the AC group (30.0% vs. 78.0%. p = 0.003). (5) Conclusions: The collaborative deprescribing service in CB-PCT effectively identified and deprescribed MRPs that are clinically significant and implementable in practice.

Study Protocol for the Evaluation of Multidisciplinary Medication Reconciliation Service in Adult Patients Undergoing Thoracic and Cardiovascular Surgery (The MERITS Study): A Single-Center Controlled before-and-after Study.

Medication reconciliation (MR), which is widely implemented worldwide, aims to improve patient safety to reduce the medication errors during care transition. Despite its widespread use, MR has not yet been implemented in the Republic of Korea, and its effectiveness has not been studied. We aimed to evaluate the impact of a multidisciplinary MR service in older patients undergoing thoracic and cardiovascular surgery. This is a single-center, prospective, controlled, before-and-after study of adult patients taking at least one chronic oral medication. Depending on the period of each patient's participation, they will be allocated to an intervention group or control group. Patients in the intervention group will receive multidisciplinary MR, and those in the control group will receive usual care. The primary outcome is to assess the impact of the MR service on medication discrepancies between the best possible medication history and medication orders at care transition. Secondary outcomes include the incidence rate of medication discrepancies at each transition, the discrepancy rate between the sources of information, the impact of MR on medication appropriateness index score, drug-related problems, 30-day mortality, the emergency department visit rate, readmission rate after discharge, the rate and acceptability of pharmacists' intervention during hospitalization, and patients' satisfaction.

Clinical impacts of the concomitant use of L-asparaginase and total parenteral nutrition containing L-aspartic acid in patients with acute lymphoblastic leukemia.

Introduction: L-asparaginase (ASNase) depletes L-asparagine and causes the death of leukemic cells, making it a mainstay for the treatment of acute lymphoblastic leukemia (ALL). However, ASNase's activity can be inhibited by L-aspartic acid (Asp), which competes for the same substrate and reduces the drug's efficacy. While many commercially used total parenteral nutrition (TPN) products contain Asp, it is unclear how the concomitant use of TPNs containing Asp (Asp-TPN) affects ALL patients treated with ASNase. This propensity-matched retrospective cohort study evaluated the clinical effects of the interaction between ASNase and Asp-TPN. Methods: The study population included newly diagnosed adult Korean ALL patients who received VPDL induction therapy consisting of vincristine, prednisolone, daunorubicin, and Escherichia coli L-asparaginase between 2004 and 2021. Patients were divided into two groups based on their exposure to Asp-TPN: (1) Asp-TPN group and (2) control group. Data, including baseline characteristics, disease information, medication information, and laboratory data, were collected retrospectively. The primary outcomes for the effectiveness were overall and complete response rates. Relapse-free survival at six months and one year of treatment were also evaluated. The safety of both TPN and ASNase was evaluated by comparing liver function test levels between groups. A 1:1 propensity score matching analysis was conducted to minimize potential selection bias. Results: The analysis included a total of 112 ALL patients, and 34 of whom received Asp-TPN and ASNase concomitantly. After propensity score matching, 30 patients remained in each group. The concomitant use of Asp-TPN and ASNase did not affect the overall response rate (odds ratio [OR] 0.53; 95% confidence interval [CI] = 0.17-1.62) or the complete response rate (OR 0.86; 95% CI = 0.29-2.59) of the ASNase-including induction therapy. The concomitant use of Asp-TPN and ASNase also did not impact relapse-free survival (RFS) at six months and one year of treatment (OR 1.00; 95% CI = 0.36-2.78 and OR 1.24; 95% CI, 0.50-3.12, respectively). The peak levels of each liver function test (LFT) and the frequency of LFT elevations were evaluated during induction therapy and showed no difference between the two groups. Conclusion: There is no clear rationale for avoiding Asp-TPN in ASNase-treated patients.

Evaluation of Low-Molecular-Weight Heparin for Treatment of Portal Vein Thrombosis in Liver Cirrhosis Patients.

Background and Objectives: Even though low-molecular-weight heparin (LMWH), including dalteparin, has a critical role in portal vein thrombosis (PVT) treatment in liver cirrhosis (LC) patients, the predictive factors and the proper dose of dalteparin for PVT treatment and relapse have not yet been investigated. Materials and Methods: This retrospective study evaluated the records of LC patients receiving dalteparin from July 2013 to June 2019. The odds ratio (OR) and adjusted OR were calculated from univariate and multivariable analyses, respectively. Results: Among data from 121 patients, the overall recanalization rate of all patients was 66.1% (80 patients). No history of variceal bleeding (OR 4.6, 95% CI: 1.88-11.43) and the case of newly developed thrombus before dalteparin treatment (OR 3.2, 95% CI: 1.24-8.08) were predictive factors associated with increased treatment response. Relapse of PVT occurred in 32 out of 80 patients (40%) who showed a recanalization. The risk of relapse was 3.1-3.9 times higher in those who took more than three months or more than six months from the diagnosis of PVT to dalteparin treatment compared to those who took less than these durations, respectively. In the dosing regimen, patients with the kg-based dosing regimen showed 2.6 times better response than those with the fixed dosing regimen. However, no difference in bleeding complications was observed. Conclusion: In the dosing regimen, the kg-based regimen that was the same as the venous thromboembolism regimen was a better option for the efficacy and safety of dalteparin therapy. Additionally, when treating PVT in LC patients, careful monitoring is recommended for patients with predictive factors for treatment response and relapse of PVT.

Prognostic Significance of the Severity of Immune-Related Adverse Events in Advanced Cancer Patients Treated with PD-1/PD-L1 Inhibitors: A Real-World Data Analysis.

BACKGROUND: There is limited evidence regarding immune-related adverse events (irAEs) in Asian cancer patients treated with antibodies directed against programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1). OBJECTIVE: This study aimed to investigate the clinical patterns and prognostic significance of grade 1-2 and grade ≥ 3 irAEs by PD-1/PD-L1 inhibitors in cancer patients using real-world clinical data. PATIENTS AND METHODS: We conducted a retrospective study of cancer patients who received pembrolizumab, nivolumab, or atezolizumab at a tertiary hospital in South Korea. Incidence, time to onset, and grade 1-2 and grade ≥ 3 irAE risk factors were analyzed from medical records. The association of irAE severity with progression-free survival (PFS) and prognostic factors for PFS were evaluated. RESULTS: Among a total of 431 patients, irAEs occurred in 45.2%, and 9.5% were grade ≥ 3 irAEs. There were no significant differences in the median time to onset based on severity. Risk factors for the development of grade ≥ 3 irAEs were the presence of autoimmune disorders or diabetes mellitus. The median PFS was significantly different at 13.20, 9.00 and 4.17 months for the grade 1-2, grade ≥ 3, and no irAE groups, respectively. An increase in administration cycles was associated with a reduced risk of progression in patients with grade 1-2 and grade ≥ 3 irAEs. CONCLUSIONS: The development of grade ≥ 3 irAEs was affected by comorbidities and associated with improved PFS compared with those without irAEs. Our findings identified the real-world epidemiology, risk factors, and prognostic significance of irAEs, which may guide treatment decisions of PD-1/PD-L1 inhibitors.

Clinical and Economic Impact of Pharmacists' Intervention on Care of Pediatric Hematology and Oncology Patients.

INTRODUCTION: Children with cancer may be one of the most vulnerable groups to drug-related adverse events because they possess characteristics of patients with cancer as well as pediatric patients. To evaluate the clinical and economic impact of pharmacists' intervention on the care of pediatric hematology and oncology patients in the inpatient and outpatient settings of a children's hospital. METHODS: The pharmacist-intervention records from 2017 were retrospectively reviewed. Intervention rate, type of drug-related problems, acceptance rate, and frequently involved drugs in pharmacist interventions were analyzed. One physician and one pharmacist evaluated the clinical significance of each intervention. A cost-benefit analysis was conducted from hospital and patient perspective. The benefit from cost savings by reducing the number of prescribed drugs that are disposed was estimated as the benefit from hospital perspective. The benefit from cost avoidance based on the potential to avoid an adverse drug event (ADE) was estimated as the benefit from patient perspective. The cost of reviewing prescriptions was estimated based on the pharmacists' salary and the time involved. RESULTS: In 2017, 2361 interventions were performed in 381 pediatric patients with cancer. The acceptance rate was 97.2%. More than half of the interventions were regarded as clinically "significant" (58.8%) and "very significant" (14.6%). The cost-benefit of US$28,705 was determined from hospital perspective, with a cost-benefit ratio of 1.45:1. The cost-benefit of US$35,611 was calculated from patient perspective, with a cost-benefit ratio of 1.55:1. CONCLUSIONS: Pharmacists' intervention in the care of hematology and oncology pediatric patients was effective in preventing clinically significant ADEs and had a positive economic impact on the health-care budget from both hospital and patient perspective.

Long-Term Survival and Kidney Function in Pediatric Patients Following Liver Transplantation: A 15-Year Retrospective Cohort Study.

Long-term preservation of kidney function after liver transplantation (LT) has not been well studied. We thus evaluated the rates of kidney function preservation and long-term survival after pediatric LT. We also investigated the risk factors associated with the progression of chronic kidney disease (CKD). We conducted a retrospective study of 184 pediatric patients who had undergone LT from 2003 to 2018 at a university hospital. We collected demographics, primary indications for LT, liver disease scores, renal function test results, immunosuppressive drug prescriptions, and diagnosis of post-LT complications. The 15-year survival rate was 90.8%. Furthermore, the rate of kidney function preservation at 14 years post-LT in patients at high risk of renal disease was 79.3%, and that in those with less risk of kidney diseases was 96.0%. Arterial hypertension was an independent risk factor associated with CKD progression. However, when arterial hypertension was excluded, the use of cyclosporine and liver disease with renal involvement were risk factors for CKD progression. We found that kidney function after pediatric LT was well preserved. We encourage the early detection of underlying kidney involvement, routine monitoring of renal function for high-risk patients, active control of hypertension, and appropriate immunosuppressive regimens for pediatric patients with LT.

Effect of selenium-free parenteral nutrition on serum selenium of neonates and infants maintained on long-term parenteral nutrition.

BACKGROUND: The risk of selenium deficiency increases for infants receiving long-term parenteral nutrition (PN). This study analyzed selenium deficiency in neonates and infants requiring long-term PN and evaluated the effect of intravenous (IV) selenium provision. METHODS: This study was a retrospective study of neonates and infants who were admitted to a neonatal intensive care unit from January 2010 to December 2019, received PN for ≥2 weeks, and had their serum selenium concentration measured. Patients were divided into two groups, depending on their serum selenium concentration, a deficient group (n = 55) and a nondeficient group (n = 47). RESULTS: Of the study participants, 53.9% (55 of 102) were deficient in selenium. No difference in demographic and clinical characteristics existed except bronchopulmonary dysplasia. A subgroup analysis was performed for patients (n = 29). The average dose of IV selenium administered to patients was 2.7 ± 1.0 mcg/kg/day. The average initial serum selenium concentration was 36.5 ± 18.0 mcg/L, and the serum concentration significantly increased to 52.5 ± 19.1 mcg/L after IV selenium administration (P < .001). The correlation between the average IV selenium dose and the change in serum selenium concentrations was statistically significant (r = .423; P = .022). CONCLUSION: Selenium deficiency is common in neonates and infants receiving long-term PN. Serum selenium concentration increased proportionally as the IV selenium dose increased. Therefore, it is recommended to supply a proper dose of IV selenium depending on the degree of selenium deficiency.

Machine Learning Approaches to Predict Hepatotoxicity Risk in Patients Receiving Nilotinib.

Background: Although nilotinib hepatotoxicity can cause severe clinical conditions and may alter treatment plans, risk factors affecting nilotinib-induced hepatotoxicity have not been investigated. This study aimed to elucidate the factors affecting nilotinib-induced hepatotoxicity. Methods: This retrospective cohort study was performed on patients using nilotinib from July of 2015 to June of 2020. We estimated the odds ratio and adjusted odds ratio from univariate and multivariate analyses, respectively. Several machine learning models were developed to predict risk factors of hepatotoxicity occurrence. The area under the curve (AUC) was analyzed to assess clinical performance. Results: Among 353 patients, the rate of patients with grade I or higher hepatotoxicity after nilotinib administration was 40.8%. Male patients and patients who received nilotinib at a dose of ≥300 mg had a 2.3-fold and a 3.5-fold increased risk for hepatotoxicity compared to female patients and compared with those who received <300 mg, respectively. H2 blocker use decreased hepatotoxicity by 11.6-fold. The area under the curve (AUC) values of machine learning methods ranged between 0.61-0.65 in this study. Conclusion: This study suggests that the use of H2 blockers was a reduced risk of nilotinib-induced hepatotoxicity, whereas male gender and a high dose were associated with increased hepatotoxicity.

Pharmacist-Led Collaborative Medication Management for the Elderly with Chronic Kidney Disease and Polypharmacy.

Inappropriate polypharmacy is likely in older adults with chronic kidney disease (CKD) owing to the considerable burden of comorbidities. We aimed to describe the impact of pharmacist-led geriatric medication management service (MMS) on the quality of medication use. This retrospective descriptive study included 95 patients who received geriatric MMS in an ambulatory care clinic in a single tertiary-care teaching hospital from May 2019 to December 2019. The average age of the patients was 74.9 ± 7.3 years; 40% of them had CKD Stage 4 or 5. Medication use quality was assessed in 87 patients. After providing MMS, the total number of medications and potentially inappropriate medications (PIMs) decreased from 13.5 ± 4.3 to 10.9 ± 3.8 and 1.6 ± 1.4 to 1.0 ± 1.2 (both p < 0.001), respectively. Furthermore, the number of patients who received three or more central nervous system-active drugs and strong anticholinergic drugs decreased. Among the 354 drug-related problems identified, "missing patient documentation" was the most common, followed by "adverse effect" and "drug not indicated." The most frequent intervention was "therapy stopped". In conclusion, polypharmacy and PIMs were prevalent in older adults with CKD; pharmacist-led geriatric MMS improved the quality of medication use in this population.

Clinical significance of potential drug-drug interactions in a pediatric intensive care unit: A single-center retrospective study.

Despite the high prevalence of potential drug-drug interactions in pediatric intensive care units, their clinical relevance and significance are unclear. We assessed the characteristics and risk factors of clinically relevant potential drug-drug interactions to facilitate their efficient monitoring in pediatric intensive care units. This retrospective cohort study reviewed the medical records of 159 patients aged <19 years who were hospitalized in the pediatric intensive care unit at Seoul National University Hospital (Seoul, Korea) for ≥3 days between August 2019 and February 2020. Potential drug-drug interactions were screened using the Micromedex Drug-Reax® system. Clinical relevance of each potential drug-drug interaction was reported with official terminology, magnitude of severity, and causality, and the association with the patient's clinical characteristics was assessed. In total, 115 patients (72.3%) were exposed to 592 potential interactions of 258 drug pairs. In 16 patients (10.1%), 22 clinically relevant potential drug-drug interactions were identified for 19 drug pairs. Approximately 70% of the clinically relevant potential drug-drug interactions had a severity grade of ≥3. Exposure to potential drug-drug interactions was significantly associated with an increase in the number of administrated medications (6-7 medications, p = 0.006; ≥8, p<0.001) and prolonged hospital stays (1-2 weeks, p = 0.035; ≥2, p = 0.049). Moreover, clinically relevant potential drug-drug interactions were significantly associated with ≥8 prescribed drugs (p = 0.019), hospitalization for ≥2 weeks (p = 0.048), and ≥4 complex chronic conditions (p = 0.015). Most potential drug-drug interactions do not cause clinically relevant adverse outcomes in pediatric intensive care units. However, because the reactions that patients experience from clinically relevant potential drug-drug interactions are often very severe, there is a medical need to implement an appropriate monitoring system for potential drug-drug interactions according to the pediatric intensive care unit characteristics.

Association of risk factors and bleeding complications in Asian patients taking edoxaban.

AIMS: Asian patients are known to be more prone to bleeding complications than patients of other ethnicities. Therefore, there are possibilities of other risk factors that should be given special consideration for dosage adjustment in this specific ethnic group. This study aimed to investigate the risk factors for bleeding complications in Asian patients under appropriate edoxaban dosage regimens. METHODS: Data on patients taking proper dosages, based on the Lixiana package insert, were analysed. Univariate and multivariable analyses were conducted to evaluate associations between risk factors and bleeding outcomes. Subgroup analysis was performed on high-risk patients for bleeding complications whose edoxaban dose was reduced according to the package insert. RESULTS: In total, 346 patients were included. Among them, 32 patients experienced bleeding complications. Patients with weight ≤60 kg and with cancer showed around 3.3- and 3.4-fold increased risk of bleeding complications compared to heavier patients (>60 kg) and those without cancer, respectively. In subgroup analysis with high-risk patients who took low-dose edoxaban (15 and 30 mg), weight ≤60 kg remained a significant factor for bleeding outcomes. CONCLUSION: This study showed that weight ≤60 kg and the presence of cancers could affect bleeding complications, which occurred despite proper edoxaban treatment in Asian patients. Therefore, more strict dosage guideline could be considered in populations with high proportions of Asian ethnicities.

Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study.

PURPOSE: Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I-II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III-IV) hepatotoxicity of TKIs. METHODS: This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. RESULTS: Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255-3.944) and 3.3-fold (95% CI 1.260-8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561-7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106-0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. CONCLUSION: The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

Effect of post-operative anticoagulation management in patients who have undergone On-X mechanical heart valve replacement surgery on post-discharge warfarin therapy.

WHAT IS KNOWN AND OBJECTIVE: We evaluated the effect of the proportion of time maintained within the target international normalized ratio (INR) postoperatively in hospitalized patients who underwent On-X mechanical heart valve replacement on warfarin therapy after discharge. METHODS: Inclusion was patients who were ≥18 years, received warfarin for a minimum of 10 days without any interruptions during hospitalization and followed by the anticoagulation service (ACS) clinic after discharge between June 2006 and June 2016. Patients were excluded if they had incomplete medical records, INR goal changes, known as warfarin resistance, transferred to another facility or expired during the study. The patients were divided into 3 groups according to the proportion of time maintained within therapeutic INR range (TTR) from day 4 to 10 of warfarin initiation (low: <30%, moderate: ≥30% to <70%, and high: ≥70%). The number of days needed to reach target INR for 2 consecutive measurements after discharge and the number of ACS visits was compared among the groups. RESULTS AND DISCUSSION: Among 539 postoperative patients, 273 were included. The baseline demographics were similar among the 3 groups. The mean time needed to reach target INR for 2 consecutive measurements was 68.6 ± 106.1 days. The low group required time needed to reach target INR for 2 consecutive measurements of 94.0 ± 140.9 days compared with 44.8 ± 57.1 days in the high group (P = .007). Additionally, the low group had more ACS visits than the high group (low, 6.6 ± 5.2 vs high, 4.6 ± 3.9; P = .025). Patient compliance affected the time needed to reach target INR for 2 consecutive measurements (compliant, 42.36 ± 58.5 days vs non-compliant, 132.0 ± 157.1 days, P < .001). WHAT IS NEW AND CONCLUSION: The study implicated that high postoperative TTR would reduce the time to require post-discharge target INR and the number of ACS visits.

Factors Influencing Imatinib-Induced Hepatotoxicity.

PURPOSE: Although imatinib-induced hepatotoxicity may aggravate the patient's clinical condition and alter the treatment plan, the underlying mechanism of and factors influencing imatinibinduced hepatotoxicity have rarely been investigated. The purpose of this study was to investigate factors affecting on the incidence of hepatotoxicity within 90 days after starting imatinib treatment and time to onset of imatinib-induced hepatotoxicity. MATERIALS AND METHODS: We retrospectively evaluated the records of 177 patients receiving imatinib from October 2012 to September 2017. The analyzed factors included sex, age, body weight, body surface area, underlying disease, and concomitant drugs. RESULTS: The proportion of patients with hepatotoxicity within 90 days after imatinib administration was 33.9%. Proton pump inhibitors (PPIs) increased the incidence of hepatotoxicity approximately 3.8-fold and doubled the hazard of time to reach hepatotoxicity. Patients with liver disease or hepatitis B virus (HBV) carriers had a more than 8-fold higher risk of hepatotoxicity and a 5.2-fold increased hazard of hepatotoxicity compared to those without liver disease or HBV. Patients with body weight under 55 kg had a 2.2-fold higher risk for occurrence of hepatotoxicity. Patients with an imatinib dose > 400 mg had a 2.3-fold increased hazard of time to reach hepatotoxicity compared to those with an imatinib dose ≤ 400 mg. CONCLUSION: The findings of this study suggest that the use of PPIs and presence of liver disease or HBV were associated with imatinib-induced hepatotoxicity. Thus, close liver function monitoring is recommended, especially in patients with liver impairment or using PPIs.

Factors related to inappropriate edoxaban use.

WHAT IS KNOWN AND OBJECTIVE: The aim of this study was to evaluate the appropriateness and clinical outcomes of edoxaban use, and to determine the role of clinical pharmacists in improving the efficacy and safety of edoxaban use. METHODS: A retrospective study was performed by using an electronic medical record and anticoagulation clinical data from 600 patients who received edoxaban from 1 March 2016 to 16 July 2017 at a tertiary teaching university hospital. The appropriateness of edoxaban use was assessed using eight criteria based on drug use evaluation criteria developed by the American Society of Health-System Pharmacists drug use evaluation guidelines, details in Korea Food and Drug Administration approval of edoxaban. Clinical outcomes were evaluated between the appropriately prescribed and inappropriately prescribed groups regarding the incidence of thrombosis and bleeding episodes. RESULTS AND DISCUSSION: After excluding 86 patients due to the inability to assess renal function, 514 were eligible. Appropriate use was found in 294 patients (57.2%). The most frequent inappropriate use of edoxaban was dose adjustment (60.8%) in accordance with the dosing recommendation in patients with renal insufficiency (creatinine clearance [CrCl] of 15-50 mL/min) and a low body weight of <60 kg. Moreover, there were three cases of edoxaban use in patients with prosthetic heart valves and moderate-to-severe mitral stenosis, and 15 cases of non-valvular atrial fibrillation in patients with CrCl >95 mL/min in whom edoxaban use is not recommended. Furthermore, we found that the factors related to the appropriateness of edoxaban use were <60 kg body weight (adjusted odds ratio [OR]: 0.310; confidence interval [CI]: 0.197-0.488) and CrCl <50 mL/min (adjusted OR: 0.629; CI: 0.404-0.980). There were 45 events (8.75%) of any bleeding, 9 (1.8%) of stroke/transient ischaemic attack (TIA) and four events (0.8%) of deep vein thrombosis (DVT)/pulmonary embolism (PE). However, there was no difference between the appropriately prescribed group (294 patients) and inappropriately prescribed group (220 patients) in the incidence of bleeding events (27 [9.2%] vs 18 [8.2%]), stroke/TIA (7 [2.4%] vs 2 [0.9%]) and DVT/PE (2 [0.7%] vs 2 [0.9%]), respectively. WHAT IS NEW AND CONCLUSION: Although edoxaban has a broad therapeutic window that does not require routine monitoring, it should be cautiously used in patients with renal insufficiency (CrCl <50 mL/min) and body weight <60 kg.

Effects of cyclic parenteral nutrition on parenteral nutrition-associated cholestasis in newborns.

BACKGROUND AND OBJECTIVES: Parenteral nutrition (PN) is one of the main nutritional methods used in newborns; however, long-term PN may induce PN-associated cholestasis (PNAC). This study aims to evaluate the effect of cyclic PN in the prevention and improvement of PNAC in newborns requiring long-term PN. METHODS AND STUDY DESIGN: A retrospective cohort study was conducted on patients admitted at the Seoul National University Children's Hospital neonatal intensive care unit between October 2010 and September 2015 and referred to the nutrition support team with total parenteral nutrition for more than 14 days. The primary outcome was the incidence of PNAC. The incidence of hypoglycemia, changes in direct bilirubin (DB) concentrations, and length of hospital stay were investigated. RESULTS: A total of 124 patients were observed in this study. Among these, 100 patients received continuous PN, whereas 24 patients received both continuous and cyclic PN. PNAC occurred in 31.5% (39/124) of study population. The incidence rates of PNAC were 27.4% during continuous PN period and 20.8% during cyclic PN period. Cyclic PN was an independent factor that significantly decreased PNAC incidence (OR=0.154; 95% CI, 0.045-0.529, p=0.003). DB concentrations significantly decreased (p=0.049) with therapeutic cyclic PN, but remained normal with prophylactic cyclic PN. No significant difference in hypoglycemia incidence and length of hospital stay was observed in both continuous PN and continuous to cyclic PN groups. CONCLUSIONS: Cyclic PN could be effective in the prevention and improvement of PNAC and also safe in terms of hypoglycemia in newborns.

Surveillance of adverse drug events associated with etanercept prescribed for juvenile idiopathic arthritis in a single center up to 9-years: A retrospective observational study.

The introduction of biologic agents opened a new era of treatment of juvenile idiopathic arthritis (JIA) over the past decade. From clinical experience, it appears that biological agents are well tolerated overall, and serious adverse events are rare. However, such clinical studies have not been conducted in Korea. Therefore, we examined the safety profile of JIA patients with biologics in a single center in Korea. All JIA outpatients treated from April 2004 to June 2013 were enrolled and retrospectively reviewed. Pharmacy-based surveillance of adverse drug events (ADEs) was identified by recording the patient's symptoms in the medical record and suspected ADEs were additionally explored by screening laboratory test values and observing changes in medication orders. Finally, 83 patients were enrolled and experienced 109 ADEs in 52 patients. Most ADEs (99.1%) were mild to moderate in severity assessment. The total follow-up time was 328 patient-treatment years and the overall rate of ADEs was 0.33 per patient-years for etanercept. Infection including upper respiratory tract was the most common ADE and concomitant corticosteroids contributed to the risk of infections. If the dose of prednisolone increases 0.34 mg/kg/day, the probability of developing infections increases 3.29 times. Also, all 11 patients who stopped etanercept with injection site reactions were receiving a single use prefilled syringe. In our study, etanercept appears well tolerated and safe. Children affected by JIA should be carefully monitoring so as to limit the risk of ADEs during etanercept as much as possible. To gain further knowledge about risk profiles, national collaboration for the accumulation of long-term data should be encouraged in Korea.

Risk factors for erlotinib-induced hepatotoxicity: a retrospective follow-up study.

BACKGROUND: Erlotinib is a drug used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer. Severe hepatotoxicity was observed in 4% to 31% of patients receiving erlotinib treatment prompting delay or termination of treatment. Only a few factors related to hepatotoxicity of erlotinib have been reported. No study has investigated the role of concomitant medications and erlotinib-induced hepatotoxicity. The aim of this study was to investigate the association between erlotinib-induced hepatotoxicity and various factors including concomitant medications in patients with NSCLC and pancreatic cancer. METHODS: From January 2014 to June 2017, a retrospective study was conducted in patients with NSCLC and pancreatic cancer, who were treated with erlotinib. Various data were reviewed, including sex, age, body weight, height, body surface area (BSA), underlying disease, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), smoking history, erlotinib dose, EGFR mutation, and concomitant drugs. RESULTS: The incidence of grade 2 or higher hepatotoxicity in the study group of patients was 17.2%. Multivariate analysis showed a 2.7-fold increase in hepatotoxicity with the concomitant use of CYP3A4 inducers. In NSCLC patients, co-administration of H2-antagonist/PPI increased hepatotoxicity 3.5-fold. Among the demographic factors, liver metastasis and age ≥ 65 years were significant risk factors in all study patients and NSCLC patients, respectively; the attributable risks for liver metastasis and age were 46.3% and 71.8%, respectively. Subgroup analysis using pancreatic cancer patients yielded marginally significant results with CYP3A4 inducers and erlotinib-induced hepatotoxicity. Liver metastasis and CYP3A4 inducers also shortened time to hepatotoxicity 2.1 and 2.3-fold, respectively. CONCLUSIONS: Our study showed that concomitant use of CYP3A4 inducers and H2-antagonist/PPI, liver metastasis, and age ≥ 65 were associated with erlotinib-induced hepatotoxicity. Thus, close monitoring of liver function is recommended, especially in patients using CYP3A4 inducers and anti-acid secreting agents.