Eunhee Ji

Combinational effect of intestinal and hepatic CYP3A5 genotypes on tacrolimus pharmacokinetics in recipients of living donor liver transplantation.

Background For living donor liver transplantation, the genetic association of CYP3A5 genotype of recipient’s native intestine and donor’s liver allograft with tacrolimus pharmacokinetics has not been explained completely considering liver regeneration time. The goal of the study was to investigate the longitudinal effects of recipient-donor combinational CYP3A5 genotypes on tacrolimus dose-normalized concentration (C/D ratio) in blood. Methods Tacrolimus blood concentrations were measured for 58 Korean adult living donor liver transplant recipients on tacrolimus-based immunosuppressants during 4 years of follow-up. CYP3A5 was genotyped for both recipient and donor, and the recipient-donor combinational genetic effect on tacrolimus C/D ratios were evaluated as a function of time after adjusting for covariates including demographics and clinical variables. Results CYP3A5 expresser recipients grafted from CYP3A5 expresser donors consistently had the least C/D ratio throughout the entire study period, whereas CYP3A5 expresser recipients grafted from CYP3A5 nonexpresser donors had an intermediate, and CYP3A5 nonexpresser recipients grafted from CYP3A5 nonexpresser donors had the largest C/D ratio (all P < 0.01). The CYP3A5 nonexpresser recipients grafted from CYP3A5 expresser donors showed a significant decrease from the largest to the intermediate in C/D ratio for the first month. Conclusions CYP3A5 genotypes of both recipient and donor were important factors influencing pharmacokinetic variability of tacrolimus. The recipient-donor combinational genetic effect on C/D ratio changed over time after transplantation.

Identification of Factors Affecting Tacrolimus Level and 5-Year Clinical Outcome in Kidney Transplant Patients

The purpose of this study was to identify and characterize the association of various clinical variables and CYP3A5 genotypes with the pharmacokinetics of tacrolimus and outcome over 1–5 years in kidney transplantation patients in Korea. A total of 129 recipients (aged 18–65 years) administered tacrolimus were genotyped for CYP3A5 (6986A>G in intron 3; rs776746). Clinical covariates and trough levels, doses and dose‐adjusted trough levels of tacrolimus, as well as complications during the 1–5 years after transplantation, were analysed. A linear mixed model was used to investigate potential factors affecting the trough levels, doses and dose‐adjusted levels of tacrolimus. We identified factors affecting chronic allograft nephropathy (CAN) and tacrolimus‐related complications. After adjusting for sex, body‐weight and doses of corticosteroids and mycophenolate mofetil, we noted that CYP3A5 genotypes had the most profound effect on the dose and dose‐adjusted trough levels of tacrolimus 1–5 years after transplantation (p < 0.001). Trough levels of tacrolimus were associated with post‐transplantation hyperlipidaemia (p < 0.05), and estimated glomerular filtration rate was associated with CAN (p < 0.05). Therefore, the CYP3A5 genotype is a variable marker for tacrolimus dose requirement, and the trough level of tacrolimus should be controlled to minimize post‐transplant hyperlipidaemia to achieve optimum outcome.

Population pharmacokinetics and pharmacodynamics of busulfan with GSTA1 polymorphisms in patients undergoing allogeneic hematopoietic stem cell transplantation.

AIM A population pharmacokinetic (PPK) analysis was conducted to describe the influence of GSTA1 polymorphisms on intravenous busulfan in adults undergoing allogeneic hematopoietic stem cell transplantation. PATIENTS & METHODS A PPK model was developed from 36 patients by a one-compartment model with first-order elimination. RESULTS The typical value of clearance and volume of distribution were 11.0 l/h and 42.4 l, respectively. Clearance decreased by 15% and area under the concentration-time curves (AUCs) increased with GSTA1 variants compared with wild-type (both p < 0.05). Subtherapeutic AUCs were seen only in wild-type patients. CONCLUSION To our knowledge, this is the first PPK study to suggest that GSTA1 polymorphisms in adults are associated with busulfan PK.

Pharmacogenomic biomarker information in FDA-approved paediatric drug labels.

Gene maturation differs between paediatric and adult populations, and the extrapolation of adult pharmacogenomic information to paediatrics is not always appropriate. We sought to determine the extent of paediatric pharmacogenomic trial translation into US FDA‐approved labels and to evaluate needs for biomarker studies. Using FDAs Table of Genomic Biomarkers and Drugs@FDA website, 38 pharmacogenomic biomarkers in 56 drug labels were identified with possible application in paediatrics. Of these 56 drugs, biomarker comparison against ‘Very Important Pharmacogenes (VIPs)’ defined in PharmGKBs database revealed a total of eight VIPs labelled among 41 drugs. One hundred and thirty‐nine product reviews posted on the FDA website under the Best Pharmaceuticals for Children Act and Paediatric Research Equity Act between October 2007 and July 2014 were examined. Review screening identified 43 drugs with ‘pharmacogenomic’ content, of which only three were true genotyping study reviews for proton pump inhibitors, all evaluating CYP2C19 polymorphisms. Pantoprazole was the sole drug labelled with pharmacogenomic information obtained specifically from paediatric trials. Clinicaltrials.gov was searched to further evaluate the current availability of pharmacogenomic studies in the paediatric population. Of the 33,132 trials registered on Clinicaltrials.gov, 137 were labelled as paediatric pharmacogenetic and pharmacogenomic studies. Pharmacogenomic studies directly conducted in paediatric patients are lacking, and thus, pharmacogenomic biomarker information based on adult studies is commonly presented in FDA‐approved labels for use in paediatric patients. Considering differences in gene expression and physiological maturation between paediatric and adult populations, studies investigating pharmacogenomic effects specifically in paediatric patients should be conducted whenever significant biomarkers are available.

A meta-analysis of the effects of interleukin-6 -174 G>C genetic polymorphism on acute graft-versus-host disease susceptibility.

BACKGROUND The interleukin-6 (IL-6) -174 G>C genetic polymorphism has been implicated to play an important role in acute graft-versus-host disease (aGVHD). However, previous studies have yielded inconclusive results as to its role in patient susceptibility to aGVHD, and no study to date has systematically analyzed this polymorphism. OBJECTIVE A meta-analysis of the published evidence was conducted to estimate the true effect of the IL-6 -174 G>C genetic polymorphism in allogeneic hematopoietic stem cell transplantation (alloHSCT) patients and donors on the risk of aGVHD. METHODS Seven cohort studies, comprising 1287 recipient and donor pairs, were included after eliminating 62 studies that met the following exclusion criteria: irrelevant studies other than cohort studies, without sufficient data, and with overlapping data. Although interstudy heterogeneity existed, most studies were conducted in the United States or Europe and included adult patients with hematologic disease who received alloHSCT from human leukocyte antigen-matched or identical sibling donors. The effect of the polymorphism on aGVHD risk (grades I-IV, II-IV, and III-IV) was estimated from odds ratios with 95% confidence intervals for the dominant genetic model and recessive model, respectively. RESULTS Patients who received grafts from donors with the IL-6 G allele experienced more frequent grade I-IV aGVHD (odds ratio = 3.304 [95% confidence interval, 1.456-7.494]) and grade II-IV aGVHD (odds ratio = 1.738 [95% CI, 1.006 - 3.001]). CONCLUSIONS To our knowledge, this is the first meta-analysis to evaluate the relation between a non-human leukocyte antigen gene polymorphism and the risk of aGVHD. Our meta-analysis combined the results of several studies and demonstrated that the donor IL-6 G allele is associated with an increased risk of grades I-IV and II-IV aGVHD.

Satisfaction and expressed needs of pharmaceutical care services and challenges recognized by patients in South Korea

Purpose To assess the degree of satisfaction and expressed needs of pharmaceutical care services in patients with chronic diseases and explore the factors related to the needs from patients’ perspectives for the further development of pharmaceutical care service models. Patients and methods A cross-sectional survey of 220 patients (mean age ± SD: 61.3±13.1, male:female: 104:116) was conducted. The questionnaire was structured to measure patients’ degree of satisfaction and expressed needs using a 5-point Likert scale. Additionally, preferred duration, methods of service delivery, and willingness to pay were surveyed. Responses were analyzed using an ordinal regression method to predict factors that were related to pharmaceutical care services. Results Sixty-seven patients had experienced pharmaceutical care services. Their satisfaction levels were high in all categories; however, there were no significant differences between categories. The levels of expressed needs were similar among categories without significant differences. The preferred delivery method was a face-to-face conversation combined with being provided with written information (53.2%). The preferred duration was ≤10 min (70.5%). About 48% of the patients showed willingness to pay for the service. Education level and region influenced patients’ needs. Conclusion The satisfaction and needs of pharmaceutical care services was very positive; however, noticing only a third of patients experienced pharmaceutical care services, this may indicate a lack of awareness and less appreciation of pharmacists by patients. Details concerning patients’ awareness and the value of pharmaceutical care services require further investigation.

Population Pharmacokinetics of Cyclosporine in Korean Adults Undergoing Living‐Donor Kidney Transplantation

Study Objective. To estimate the population pharmacokinetic parameters of cyclosporine in Korean adults undergoing living‐donor kidney transplantation, and to identify clinical factors affecting cyclosporine pharmacokinetics.

A national pharmacoepidemiological study of antibiotic use in Korean paediatric outpatients

Background Information on the use of antibiotics in Eastern Asian children is limited. The objectives of this study were to evaluate in Korean paediatric outpatients (1) the nationwide pattern of prescribing antibiotics according to age group and medical institution and (2) the adherence of antibiotic use for acute respiratory tract infections to both national guidelines and European antibiotic prescribing quality indicators. Method This population-based study used the national insurance reimbursement database for 2011. The study subjects were outpatients younger than 18 years old prescribed systemic antibiotics. Patterns of antibiotic prescription were compared according to diagnostic conditions, age group and medical institution. The disease-specific proportion of recommended antibiotic or quinolone use for acute respiratory tract infections was evaluated on the basis of clinical practice guidelines and European quality indicators. Results The data consisted of 70.7 million prescription records for 7.9 million paediatric outpatients, which means that 79.3% of the whole paediatric population used antibiotics. Broad-spectrum antibiotics made up 78.5% of the prescriptions, with broad-spectrum penicillins such as amoxicillin/clavulanate being the most commonly prescribed (50.2%). They were prescribed more commonly in younger paediatric patients (∼80%) than in adolescents (66.6%). The leading diagnosis accounting for antibiotic prescription was bronchitis (35.9%). The prescription proportion of recommended antibiotics in the European quality indicators was extremely low compared with the national guidelines: <0.1% for pharyngotonsillitis and 13.4% for acute otitis media. Conclusions Antibiotic use in children in Korea is inappropriately high. In addition, broad-spectrum antibiotics are used excessively.

Effect of pharmaceutical care interventions on glycemic control in patients with diabetes: a systematic review and meta-analysis

Purpose Diabetes is a chronic lifelong condition, and adherence to medications and self-monitoring of blood glucose are challenging for diabetic patients. The dramatic increase in the prevalence of diabetes is largely due to the incidence of type 2 diabetes in low- and middle-income countries (LMIc) besides high-income countries (HIc). We aimed to evaluate whether pharmacist care (PC) service model in LMIc and HIc could improve clinical outcomes in diabetic patients by performing a meta-analysis. Methods PubMed, Embase, and ProQuest Dissertations Unlimited Published Literature database were searched to find publications pertaining to pharmacist-led intervention in patients with diabetes. The inclusion criteria were as follows: 1) randomized controlled trials, 2) confirmed diabetic patients (type 1 or type 2), 3) pharmaceutical care intervention by clinical pharmacist or/and multidisciplinary team, and 4) reporting HbA1c at baseline and end of study or the mean change in these values. Results A total of 37 articles were included in the meta-analysis. The overall result was significant and in favor of PC intervention on HbA1c change (standard difference in mean values [SDM]: 0.379, 95% CI: 0.208–0.550, P<0.001). The stratified meta-analysis showed that PC was significant in both HIc (n=20; SDM: 0.351, 95% CI: 0.207–0.495) and LMIc (n=15; SDM: 0.426, 95% CI: 0.071–0.780). More than 6 months is needed to obtain adequate effects on clinical diabetes parameters. Conclusion Our study presented that an adequate duration of pharmacist-led pharmaceutical care was effective in improving HbA1c in patients with diabetes in both LMIc and HIc.

Network analysis of drug-related problems in hospitalized patients with hematologic malignancies

PurposeNetwork analysis was conducted to systematically analyze the relationship between causative drugs and types of drug-related problems (DRPs) in hospitalized patients with hematologic malignancies.MethodsA total of 1187 DRPs identified in hematology wards between 2013 and 2015 were analyzed. DRPs were classified into 11 sub-domains for problems and 35 sub-domains for causes according to Pharmaceutical Care Network Europe classification. Causative drugs were classified by Anatomical Therapeutic Chemical code. Network analytic tool was used to represent the relationship between drugs, causes, and problems. In-degree centrality (CD-in) was calculated to identify major causes of DRPs.ResultsThe following drugs accounted for more than 5% of DRP, including antibacterials (J01, 26.5%), drugs for acid-related disorders (A02, 11.5%), antiemetics (A04, 9.7%), antifungals (J02, 8.8%), and antineoplastic agents (L01, 7.0%). Inappropriate combinations (C1.3, CD-in of 161) of drugs for acid-related disorders, antifungals, and antineoplastic agents were major causes of DRPs and induced non-optimal effects of drug treatment (P1.2). Inappropriate dose adjustments (C3.6, CD-in of 151) of antibacterials lowered effects (P1.2) and increased side effects (P2.1). Missing necessary synergistic or preventive drugs, especially antiemetics, (C1.8, CD-in of 54) resulted in untreated indication (P1.4).ConclusionsDRPs were mainly related to medications for supportive care. More attention should be paid to interactions of drugs used for acid-related disorders, dose adjustment of antibacterials, and omission of antiemetics in hospitalized patients with hematologic malignancy.