Transporter Genes and statin-induced Hepatotoxicity.

PURPOSE: Hepatotoxicity has emerged as a major cause of statin treatment interruption. Although organic anion-transporting polypeptide 1B1 (SLCO1B1), multidrug resistance protein 1 (ABCB1), and breast cancer resistance protein (ABCG2) have been identified as transporters of statins, knowledge of their role in statin-associated hepatotoxicity remains limited. Therefore, we aimed to conduct a comprehensive analysis to elucidate the association between hepatotoxicity and SLCO1B1, ABCB1, and ABCG2 polymorphisms. METHODS: This study retrospectively analyzed prospectively collected samples. We selected 10 single nucleotide polymorphisms (SNPs) of SLCO1B1, 9 SNPs of ABCB1, and 12 SNPs of ABCG2. We developed two models for multivariable analyses (Model I: clinical factors only; Model II: both clinical and genetic factors), and the attributable risk (%) of variables in Model II was determined. RESULTS: Among 851 patients, 66 (7.8%) developed hepatotoxicity. In Model I, lipophilic statins, atrial fibrillation (Afib), and diabetes mellitus showed a significant association with hepatotoxicity. In Model II, lipophilic statins and Afib, SLCO1B1 rs11045818 A allele, SLCO1B1 rs4149035 T allele, and ABCG2 rs2622629 TT genotype were associated with higher hepatotoxicity risk. Among them, the SLCO1B1 rs11045818 A allele exhibited the highest attributable risk (93.2%). The area under the receiver operating characteristic curve in Model I was 0.62 (95% CI: 0.55-0.69), and it was increased to 0.71 in Model II (95% CI: 0.64-0.77). CONCLUSION: This study investigated the correlation between hepatotoxicity and polymorphisms of transporter genes in patients taking statins. The findings could help improve personalized treatments for patients receiving statin therapy.

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.

Association between SLCO1B1 polymorphism and methotrexate-induced hepatotoxicity: a systematic review and meta-analysis.

Reports on the association between the solute carrier organic anion transporter 1B1 (SLCO1B1) T521C polymorphism and methotrexate-induced hepatotoxicity in patients with malignancies are inconsistent. This meta-analysis evaluated the association between the SLCO1B1 T521C polymorphism and methotrexate-induced hepatotoxicity. We performed a systematic review of previous reports from the PubMed, Web of Science, and EMBASE databases, and a meta-analysis was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the effect of the SLCO1B1 T521C polymorphism on the occurrence of methotrexate-induced hepatotoxicity. In total, data from five studies including 465 patients were analyzed. Patients had received a high-dose methotrexate regimen (1-5 g/m2). The SLCO1B1 variant allele (C allele) carriers had a 1.9-fold higher risk of hepatotoxicity than wild-type homozygote carriers (TT; OR, 1.94; 95% CI, 1.14-3.31). This meta-analysis demonstrated that C allele carriers of the SLCO1B1 polymorphism had a higher risk of hepatotoxicity than patients with the TT genotype. The SLCO1B1 T521C polymorphism may be a useful predictor for methotrexate-induced hepatotoxicity in patients with malignancies.

Proton pump inhibitor use and hearing loss in patients with type 2 diabetes: Evidence from a hospital-based case-control study and a population-based cohort study.

OBJECTIVES: This study aimed to investigate the association between proton pump inhibitor (PPI) use and risk of sensorineural hearing loss (SNHL) or tinnitus in patients with type 2 diabetes using hospital- and population-based data. METHODS: For the case-control study using the Asan Biomedical Research Environment database, the characteristics between cases and sex-, age- and index-year-matched controls were compared by the chi-squared test. Conditional logistic regression was used to estimate the odds ratios (ORs). For the cohort study using the Korean National Health Insurance Service - National Sample Cohort, the hazard ratios (HRs) for SNHL or tinnitus associated with PPI use were analysed by the Cox proportional hazard regression model. RESULTS: The case-control study included 1379 cases and 5512 matched controls. After adjustment, PPI use was associated with an increased risk of SNHL or tinnitus (OR 1.61, 95% confidence interval [CI] 1.30-1.99). The ORs were higher for current or recent use of PPI and high average daily dose. In the cohort study including 17 233 pairs of PPI users and nonusers after propensity score matching, the risk of SNHL or tinnitus increased in PPI users compared with nonusers (HR 1.50, 95% CI 1.40-1.61). In the stratified analyses, risks remained significant and the magnitude of association was relatively high in those of younger age, patients without gastroesophageal reflux disease and patients not receiving histamine 2 receptor blockers. CONCLUSIONS: Our study suggests that PPI use is associated with an increased risk of SNHL or tinnitus. Given the widespread use of PPIs, the potential ototoxic effects of PPIs remain an important concern.

Antihypertensive drug use and psoriasis: A systematic review, meta- and network meta-analysis.

AIMS: Diverse genetic and/or external factors may induce psoriasis. Drug exposure is 1 such prominent external factor; antihypertensive drugs are reportedly associated with psoriasis, but study results have been inconsistent. In this context, we investigated the associations between antihypertensive drugs and incidence if psoriasis via a systematic literature review and meta-analysis. METHODS: Literature search in databases such as PubMed, Embase and Web of Science was conducted on 8 January 2021, and obtained data were pooled for meta- and network meta-analysis. Fixed- or random effect models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for evaluating the strength of the associations between antihypertensive drugs and psoriasis incidence. In addition to meta-analysis, Bayesian network meta-analysis was performed. ResultsThirteen eligible studies were included for meta-analysis with 6 378 116 individuals and 8 studies for network meta-analysis with 5 615 918 individuals. All antihypertensive drugs were significantly associated with psoriasis incidence. In a meta-analysis, the pooled ORs were 1.67 (95% CI: 1.31-2.13) for angiotensin-converting enzyme (ACE) inhibitors, 1.40 (95% CI: 1.20-1.63) for ß-blockers, 1.53 (95% CI: 1.23-1.89) for calcium-channel blockers (CCBs), and 1.70 (95% CI: 1.40-2.06) for thiazide diuretics. For the comparative risks of psoriasis among antihypertensive drugs in the network meta-analysis, ORs were 2.09 (95% CI: 1.39-3.18) for ACE inhibitors, 1.35 (95% CI: 0.99-1.91) for BBs, 1.53 (95% CI: 1.07-2.24) for CCBs and 1.80 (95% CI: 1.23-2.66) for thiazide diuretics. CONCLUSION: This study confirmed the associations between antihypertensive drugs and psoriasis; ACE inhibitors, BBs, CCBs and thiazide diuretics increased the risk of psoriasis. Therefore, antihypertensive drug users should be carefully monitored for psoriasis.

Risk factors for vancomycin-associated acute kidney injury: A systematic review and meta-analysis.

AIMS: This systematic literature review and meta-analysis aimed to evaluate the risk factors for vancomycin-associated acute kidney injury (AKI) incidence. METHODS: This study assessed risk factors for vancomycin-associated AKI in adult patients by searching studies from PubMed, the Cochrane Library and Embase. Random effect models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Fifty-three studies were included in our meta-analysis. For patient factors, black race (OR 1.47, 95% CI: 1.16-1.87), Caucasian (OR 0.72, 95% CI: 0.58-0.90) and obesity (OR 1.46, 95% CI: 1.12-1.90) were associated with an increase in vancomycin-associated AKIs. In terms of vancomycin-related factors, longer treatment duration (>14 d; OR 1.73, 95% CI: 1.06-2.83), serum vancomycin trough level >15 µg/mL (OR 2.10, 95% CI: 1.43-3.07) and vancomycin trough level >20 µg/mL (OR 2.84, 95% CI: 1.48-5.44) increased the risks of vancomycin-associated AKI. For comorbidities and clinical factors, renal disease (OR 2.19, 95% CI: 1.51-3.17) showed the highest odds of vancomycin-associated AKI, followed by hepatic disease, intensive care unit admission, heart failure, sepsis, coronary heart disease and diabetes mellitus. For concomitant nephrotoxic drugs, amphotericin B (OR 5.21, 95% CI: 3.44-7.87) showed the highest odds of vancomycin-associated AKI, followed by acyclovir (OR 3.22, 95% CI: 1.39-7.46), vasopressors, loop diuretics, piperacillin-tazobactam and aminoglycoside. The use of any concomitant nephrotoxic agent (OR 1.74, 95% CI: 1.17-2.58) increased the odds of vancomycin-associated AKI. CONCLUSION: Our results may help predict the risk of vancomycin-associated AKI in the clinical setting.

Short-term exposure to air pollution and hospital admission for pneumonia: a systematic review and meta-analysis.

BACKGROUND: Air pollution is a major issue that poses a health threat worldwide. Although several studies investigated the adverse effects of air pollution on various diseases, few have directly demonstrated the effects on pneumonia. Therefore, we performed a systematic review and meta-analysis on the associations between short-term exposure of air pollutants and hospital admission or emergency room (ER) visit for pneumonia. METHODS: A literature search was performed using PubMed, Embase, and Web of Science up to April 10, 2020. Pooled estimates were calculated as % increase with 95% confidence intervals using a random-effects model. A sensitivity analysis using the leave-one-out method and subgroup analysis by region were performed. RESULTS: A total of 21 studies were included in the analysis. Every 10 µg/m3 increment in PM2.5 and PM10 resulted in a 1.0% (95% CI: 0.5-1.5) and 0.4% (95% CI: 0.2-0.6) increase in hospital admission or ER visit for pneumonia, respectively. Every 1 ppm increase of CO and 10 ppb increase of NO2, SO2, and O3 was associated with 4.2% (95% CI: 0.6-7.9), 3.2% (95% CI: 1.3-5.1), 2.4% (95% CI: - 2.0-7.1), and 0.4% (95% CI: 0-0.8) increase in pneumonia-specific hospital admission or ER visit, respectively. Except for CO, the sensitivity analyses yielded similar results, demonstrating the robustness of the results. In a subgroup analysis by region, PM2.5 increased hospital admission or ER visit for pneumonia in East Asia but not in North America. CONCLUSION: By combining the inconsistent findings of several studies, this study revealed the associations between short-term exposure of air pollutants and pneumonia-specific hospital admission or ER visit, especially for PM and NO2. Based on the results, stricter intervention policies regarding air pollution and programs for protecting human respiratory health should be implemented.

TGF-ß1 polymorphism increases the risk of bleeding complications in patients on oral anticoagulant after cardiac valve replacement.

Although an elevated INR is highly associated with an increased risk of warfarin-associated bleeding, it has been reported that some patients also experience bleeding complications at therapeutic INRs. TGF-ß1 polymorphisms has been reported to cause vascular malformations, resulting in bleeding complications, but there are few published genetic studies regarding bleeding complications in patients on warfarin therapy. This study aimed to determine if there is an association between transforming growth factor beta-1 (TGF-ß1) polymorphisms and bleeding complications in patients who maintain international normalized ratios (INRs) of 2.0-3.0 with warfarin therapy after cardiac valve replacement. Eleven single nucleotide polymorphis (SNPs) of TGF-ß1 (rs1800469, rs2241718, rs4803455, rs2241717, rs2241716, rs2241715, rs2241714, rs11083616, rs2317130, rs747857, and rs1982073) were analyzed. Univariate and multivariable analyses were conducted to evaluate the associations between genetic polymorphisms and bleeding risk. Attributable risk and the number needed to genotype (NNG) were calculated to identify the potential clinical value of genotyping. A discrimination of model was assessed via an analysis of the area under the receiver operating curve (AUROC). To test the model's goodness of fit, a Hosmer-Lemeshow test was performed. Of 142 patients, 21 experienced bleeding complications. Among analyzed single nucleotide polymorphis (SNPs) of TGF-ß1 (rs1800469, rs2241718, rs4803455, rs2241717, rs2241716, rs2241715, rs2241714, rs11083616, rs2317130, rs747857, and rs1982073), AA genotype carriers in rs2241718 had about 5.5 times more bleeding complications than those with the G allele after adjusting for other confounders. The attributable risk and NNG for rs2241718 were 81.9% and 57.8, respectively. The presence of atrial fibrillation and myocardial infarction increased bleeding complications 3.9- and 9.8-fold, compared with those without atrial fibrillation and myocardial infarction, respectively. Bleeding complications during warfarin therapy in patients with mechanical heart valves were associated with TGF-ß1 polymorphisms as well as atrial fibrillation and myocardial infarction.

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.

Effects of KCNMB2 gene polymorphisms on ritodrine therapy outcomes in women with preterm labor.

OBJECTIVE: The present prospective follow-up study aimed to evaluate the effects of KCNMB2 gene polymorphisms on ritodrine efficacy and adverse drug events (ADEs) in patients with preterm labor. METHODS: A total of 163 preterm labor patients were included in this single-center study. Nine single nucleotide polymorphisms (SNPs) in the KCNMB2 gene (rs10936979, rs7624046, rs7429015, rs7625907, rs6443559, rs9839376, rs9637454, rs11918114, and rs1382045) were assessed. The primary endpoint was time to delivery, and the secondary endpoint was ritodrine-induced ADEs. RESULTS: Patients with variant homozygotes of two SNPs (rs7624046 and rs9839376), which were in linkage disequilibrium, showed 2.06 [95% confidence interval (CI), 1.14-3.73] and 2.68 (95% CI, 1.16-6.20) times the hazard of time to delivery compared to wild-type allele carriers, respectively. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery. Regarding safety outcomes, patients with variant homozygotes of rs7625907 had fewer ADEs compared to those with other genotypes (odds ratio, 0.32; 95% CI, 0.13-0.83). CONCLUSION: This pharmacogenomic study suggests that ritodrine efficacy and ADEs are associated with KCNMB2 gene polymorphisms in patients with preterm labor.

Efficacy and safety of clopidogrel versus prasugrel and ticagrelor for coronary artery disease treatment in patients with CYP2C19 LoF alleles: a systemic review and meta-analysis.

AIM: We performed a systematic review and meta-analysis to compare the efficacy and safety of ticagrelor and prasugrel with those of clopidogrel in CYP2C19 reduced-metabolizers. METHODS: PubMed, Cochrane and Web of Science were systematically searched for randomized controlled trials or cohort studies up to January 2020. The primary endpoint was major adverse cardiovascular events (MACE), including cardiovascular (CV) death, all-cause death, myocardial infarction (MI), stent thrombosis and stroke. The secondary endpoint was bleeding. Pooled effects were measured by relative risk (RR) with 95% confidence intervals (CIs). Publication bias was evaluated with Egger's regression test and adjusted by trim and fill method. RESULTS: Twelve studies comprising 5829 CV patients with CYP2C19 loss-of-function alleles were included. Patients who received ticagrelor or prasugrel showed a lower risk of MACE than those who received clopidogrel (RR 0.524; 95% CI: 0.375, 0.731). The former also had lower risks of CV death (RR 0.409; 95% CI: 0.177, 0.946), all-cause death (RR 0.441; 95% CI: 0.263, 0.739), MI (RR 0.554; 95% CI: 0.414, 0.741) and stent thrombosis (RR 0.587; 95% CI: 0.348, 0.988) than the latter patient group. The risk of stroke was not significantly different between patients receiving the alternatives and those receiving clopidogrel (RR 0.605; 95% CI: 0.257, 1.425). Major and minor bleeding risk was not significantly different between patients treated with alternatives and clopidogrel (RR 1.019; 95% CI: 0.827, 1.260 and RR 1.235; 95% CI: 0.581, 2.628, respectively). CONCLUSION: CYP2C19 reduced-metabolizers can expect better clinical outcome on using prasugrel or ticagrelor rather than clopidogrel.

Population Pharmacokinetics of Sulindac and Genetic Polymorphisms of FMO3 and AOX1 in Women with Preterm Labor.

PURPOSE: This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor. METHODS: Plasma samples were collected at 1.5, 4, and 10 h after first oral administration of sulindac. Plasma concentrations of sulindac and its active metabolite (sulindac sulfide) were determined, and pharmacokinetic analysis was performed with NONMEM 7.3. RESULTS: The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20-41) years and 27.4 ± 4.4 (range, 16.4-33.4) weeks, respectively. In the population pharmacokinetic analysis, one depot compartment model of sulindac with absorption lag time best described the data. The metabolism of sulindac and sulindac sulfide was described using Michaelis-Menten kinetics. In stepwise modeling, gestational age impacted volume of distribution (Vc), and FMO3 rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model. CONCLUSIONS: Genetic polymorphisms of FMO3 and AOX1 could affect the pharmacokinetics of sulindac in women who undergo preterm labor. The results of this study could help clinicians develop individualized treatment plans for administering sulindac.

Factors Associated With Voriconazole Concentration in Pediatric Patients.

BACKGROUND: Serum concentrations of voriconazole are difficult to predict, especially in pediatric patients, because of its complex pharmacokinetic characteristics. This study aimed to identify the factors associated with the concentration of voriconazole in pediatric patients. METHODS: This cohort study was based on retrospective data collection and involved the administration of voriconazole to pediatric patients younger than 18 years, between January 2010 and August 2017. Electronic medical records of the patients were reviewed to collect demographic characteristics, voriconazole treatment regimen, and factors that could potentially influence voriconazole trough concentrations. A voriconazole trough serum concentration of less than 1.0 mcg/mL or greater than 5.5 mcg/mL was defined as outside the therapeutic range and was set as the outcome of this study. RESULTS: Among the 114 patients enrolled, 61 patients were included in the analysis. Oral administration of a maintenance dose of voriconazole and C-reactive protein (CRP) level were significantly and independently associated with a low initial trough concentration of voriconazole (<1.0 mcg/mL). Alanine aminotransferase levels were a significant factor associated with a high initial trough concentration of voriconazole (>5.5 mcg/mL) after adjusting for sex, age, weight, and serum creatinine (odds ratio 5.42; 95% confidence interval 1.34-21.97). CONCLUSIONS: Considering the variability of voriconazole concentrations in pediatric patients, monitoring certain parameters and considering the route of administration could help determine the therapeutic range of voriconazole and subsequently avoid unwanted effects.

Risk factors for sodium overcorrection in non-hypovolemic hyponatremia patients treated with tolvaptan.

PURPOSE: In this study, the risk factors associated with sodium overcorrection were investigated with an optimal cutoff for baseline serum sodium for use in daily clinical practice. METHODS: Electronic medical records of patients who received tolvaptan for non-hypovolemic hyponatremia were reviewed. Demographic and clinical data including age, sex, weight, height, comorbidity, cause of hyponatremia, hypertonic saline use, and comedication were collected. Baseline laboratory parameters measured included serum sodium, serum potassium, serum creatinine, blood urea nitrogen, serum tonicity, ALT, AST, and urine osmolality. The primary outcome was the overcorrection of serum sodium, which was defined as an increase in serum sodium by more than 10 mmol/L in 24 h. RESULTS: From a total of 77 patients included in the analysis, 24 (31.2%) showed sodium overcorrection (> 10 mmol/L/24 h); 2 (2.6%) in heart failure cohort, 17 (22.1%) in SIADH cohort, and 5 (6.5%) in unknown cause cohort. More than half of patients (51.9%) were administered hypertonic saline prior to tolvaptan. Hypertension, cancer, diuretics, baseline serum sodium, and SIADH were associated with the risk of overcorrection in the univariable analysis. Significant factors for the overcorrection from multivariable analysis were lower body mass index, presence of cancer (adjusted odds ratio, 10.87; 95% CI, 1.23-96.44), and lower serum sodium at baseline (adjusted odds ratio, 0.76 for every 1 mEq/L increase; 95% CI, 0.61-0.94). CONCLUSION: The overcorrection of hyponatremia in non-hypovolemic patients treated with tolvaptan was significantly associated with lower body mass index, presence of cancer, and lower serum sodium at baseline. In subgroup analysis using SIADH patients, baseline sodium and cancer were found to be significant factors of overcorrection.

Influence of CYP2C9 and CYP2A6 on plasma concentrations of valproic acid: a meta-analysis.

PURPOSE: Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA. METHODS: The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6). RESULTS: In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-µg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-µg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01). CONCLUSION: This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA's therapeutic effect.

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.

Low cyclosporine concentrations in children and time to acute graft versus host disease.

BACKGROUND: Achievement of target blood concentrations of cyclosporine (CsA) early after transplantation is known to be highly effective for reducing the incidence of acute graft versus host disease (aGVHD). However, no research has been conducted for predicting aGVHD occurrence with low CsA concentrations at different time periods. The objective of this study was to investigate the risk of aGVHD according to low CsA concentrations at lag days in children with allogenic hematopoietic stem cell transplantation (HSCT). METHODS: The records of 61 consecutive children who underwent allogeneic HSCT and received CsA as prophylaxis against aGVHD between May 2012 and March 2015 were retrospectively evaluated. The main outcome was any association between low CsA concentrations at lag days and aGVHD occurrence, which was examined for the first month after transplantation. Mean CsA concentrations at three lag periods were calculated: lag days 0-6, 7-13, and 14-20 before aGVHD occurrence. RESULTS: Patients whose mean CsA concentrations at lag days 0-6 did not reach the initial target concentration had 11.0-fold (95% confidence interval [CI]: 2.3-51.9) greater incidence of aGVHD. In addition, the AORs of low CsA concentrations at lag days 7-13 and 14-20 for developing aGVHD were 108.2 (95% CI: 7.7-1515.5) and 12.1 (95% CI: 1.1-138.1), respectively. CONCLUSIONS: After low CsA concentrations are detected, careful attention needs to be paid to prevent aGVHD.

Effects of pharmacist interventions on reducing prescribing errors of investigational drugs in oncology clinical trials.

OBJECTIVES: This study aimed to investigate the effectiveness of pharmacist intervention in reducing and preventing prescribing errors of investigational drugs for cancer patients. MATERIALS AND METHODS: A retrospective study was conducted during two periods: a baseline period from December 2015 to June 2016 and an intervention period from July 2016 to February 2017. The investigational drug service (IDS) pharmacists performed active interventions during the intervention period. RESULTS: Among 12,387 investigational drug orders, 395 (6.1%) prescribing errors were detected in 6477 orders at the baseline period, and 278 errors (4.7%) were detected in 5,910 orders at the intervention period. To identify factors that affect prescribing errors, three models were constructed for the multivariate analysis. Among factors affecting prescribing errors, sponsor initiated trial (SIT) was the strongest factor (AOR: 4.16, 95% CI: 3.31-5.23). Pharmacist intervention reduced prescribing errors by at least 25% in all constructed models after adjusting for confounding variables. Prescribing errors were 1.3 times higher when dealing with intravenous medications than when dealing with oral medications. There were 60% fewer prescribing errors in the blinded study than in the open study. SIT and multi-center/multi-nation studies had 4.2 and 2.4 times more frequent prescribing errors than in investigator-initiated trials (IIT) and single-center/single-nation studies, respectively. Fewer errors occurred in phase 2 and trials covering both phase 1 and phase 2 (phase 1/2) than in phase 3 trials. CONCLUSIONS: The IDS pharmacist intervention in cancer clinical trials was associated with significant reductions in prescribing errors and may lead to increased medication safety.

The impact of drug interactions on adverse effects of oral oxycodone in male geriatric patients.

WHAT IS KNOWN AND OBJECTIVE: With increased opioid use, drug-drug interactions (DDIs) and associated adverse events are growing among geriatric patients. However, the clinical significance of potential metabolic DDIs associated with opioid use has not been fully evaluated among geriatric patients. Particularly, cytochrome (CYP) P450 enzymes are important in drug metabolism of oxycodone and a black box warning for oxycodone reveals serious risks associated with drug-oxycodone interactions. This study focused on the use of oxycodone in geriatric patients to evaluate its adverse drug reactions (ADRs) and DDIs associated with CYP P450 enzymes. METHODS: A retrospective cohort study using patients treated at Korea Veterans Hospital was performed. Data from male patients aged 65 years and older who received oxycodone were analysed. Binomial variables describing patient-related characteristics, drug-related characteristics and CYP-mediating drugs were constructed. Associations between these variables and the frequency of ADRs were determined. The odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariable and multivariable analyses, respectively. RESULTS AND DISCUSSION: Among 111 patients, 32.4% experienced at least one ADR. The most common ADR was gastrointestinal-related (n = 21), followed by dizziness and drowsiness (n = 8). Use of either CYP2D6 inhibitors or CYP3A4 inhibitors increased the rate of ADRs by 20.4 and 25.4 times, respectively. In the case of patients taking both inhibitors, the adjusted OR was 48.6, and the attributable risk was 97.9%. WHAT IS NEW AND CONCLUSION: This study suggests that inappropriate combinations of oxycodone with CYP2D6 inhibitors and/or CYP3A4 inhibitors may warrant treatment modification to avoid ADRs in geriatric patients. Clinicians should monitor any signs of ADRs that may reflect DDIs while a geriatric patient is taking oxycodone.

Association between HNF4A mutations and bleeding complications in patients with stable international normalized ratio.

OBJECTIVES: This study aimed to determine the association between hepatocyte nuclear factor 4 alpha (HNF4A) polymorphisms and bleeding complications in patients on warfarin with international normalized ratios between 2.0 and 3.0 after cardiac valve replacement. METHODS: Nineteen single nucleotide polymorphisms of HNF4A in addition to VKORC1 rs9934438 and CYP2C9 rs1057910 were analyzed. Univariate and multivariate analyses were conducted to evaluate associations between genetic polymorphisms and bleeding risk. Attributable risk and number needed to genotype (NNG) were calculated to assess clinical value of genotyping. RESULTS: Of 142 patients, 21 experienced bleeding complications. Multivariate logistic regression analysis was conducted using factors with P <0.1 in univariate analysis. Multivariate analysis showed that patients with the CC genotype of rs6130615 had an 8.4-fold increased risk of bleeding, compared with patients with the T allele. Attributable risk and NNG were 88.1% and 32.2, respectively. Patients with the TT genotype of rs3212191 had a 3.8-fold increased risk of bleeding, compared with C allele carriers, while patients with variant-type homozygotes for rs1884613 showed an 8.7-fold higher bleeding complication than C allele carriers. The attributable risk/NNG of rs3212191 and rs1884613 were 73.4%/17.6 and 88.5%/22.8, respectively. Among comorbidities, atrial fibrillation was the only significant risk factor for bleeding complications. CONCLUSION: Bleeding complications during warfarin therapy in patients with mechanical heart valves were associated with HNF4A polymorphisms and atrial fibrillation.