Physiologically-based pharmacokinetic modeling of nafamostat to support dose selection for treatment of pediatric patients with COVID-19

Pediatric patients with coronavirus disease 2019 (COVID-19) are increasing, and severe cases such as multisystem inflammatory syndrome are being reported. Nafamostat, a repurposing drug, is currently being explored for the treatment of COVID-19 in adults. However, the data supporting its exposure in pediatrics remains scarce. Physiologically-based pharmacokinetic (PBPK) modeling enables the prediction of drug exposure in pediatrics based on ontogeny of metabolic enzymes and age dependent anatomical and physiological changes. The study aimed to establish a PBPK model of nafamostat in adults, then scale the adult PBPK model to children for predicting pediatric exposures of nafamostat and an optimal weight-based nafamostat dose in pediatric population. The developed model adequately described adult exposure data in healthy volunteers following i.v. administration with three doses (10, 20, and 40 mg). Scaling adult PBPK models to five pediatric groups predicted that as age advances from neonate to adult, the exposure of nafamostat slightly increased from neonate to infant, steadily decreased from infant to child, and then increased from child to adult after the administration of 0.2 mg/kg/h for 14 days, a dosing regimen being conducted in a clinical trial for COVID-19. Based on the fold change of predicted area under the curve for the respective pediatric group over those of adults, weight-based dosages for each pediatric group may be suggested. The novel PBPK model described in this study may be useful to investigate nafamostat pharmacokinetics in a pediatric subgroup further.

Associations between HLA-A, -B, and -C alleles and iodinated contrast media– induced hypersensitivity in Koreans

A common cause of drug hypersensitivity reactions is iodinated contrast media (ICM). ICM-induced hypersensitivity had been considered to be a non-immunological reaction, but evidence for an immunological mechanism has increased recently. Thus, we evaluated whether HLA-A, -B, and -C alleles were associated with ICM-induced hypersensitivity. In total, 126 patients who underwent contrast-enhanced computed tomography studies through outpatient clinics at a tertiary referral hospital between 2008 and 2012 were assessed. Sixty-one patients experienced ICM-induced hypersensitivity and the remainder, 65, were ICM-tolerant patients (control). ICM-induced hypersensitivity patients showed 51 with immediate, 7 with non-immediate, 3 with both or mixed type. HLA-A, -B, and -C genotyping was performed using a PCR sequence-based typing method. Four kinds of ICM were used: iopromide, iohexol, iobitridol, and iodixanol. The most used ICM among the hypersensitivity patients was iopromide. Significant difference in the frequency of HLA-B*58:01 (odds ratios [OR], 3.90; p = 0.0200, 95% confidence interval [CI], 1.16–13.07) was observed between ICM-induced immediate hypersensitivity and control. There were statistically significant differences in the frequencies of the HLA-B*38:02 (OR, 10.24; p = 0.0145; 95% CI, 1.09–96.14) and HLA-B*58:01 (OR, 3.98; p = 0.0348; 95% CI, 1.03–15.39) between iopromide-induced immediate hypersensitivity and control. The mechanism of ICM-induced hypersensitivity remains unknown, but this study showed associations, although weak, with HLA-B*58:01 alleles for ICM-induced immediate hypersensitivity and HLA-B*38:02 and HLA-B*58:01 for iopromideinduced immediate hypersensitivity as risk predictors. Further studies are needed to validate the associations in larger samples and to identify the functional mechanism behind these results.

Survey of physicians' views on the clinical implementation of pharmacogenomics-based personalized therapy

Despite quantitative increases and qualitative advances in pharmacogenomics (PGx) research, the clinical implementation of PGx-based personalized therapy has still been limited. The objective of this study was to assess physicians' self-reported knowledge of PGx-based personalized therapy, and to explore the most problematic and highest priority barriers preventing physicians from applying PGx into clinical practice under the Korean healthcare system. A 36-question survey was distributed to 53 physicians with various specialties in Korea. In the physicians' self-perceived knowledge, twenty-eight physicians (53%) reported a lack sufficient knowledge about PGx. The perceived largest barrier to clinical implementation of PGx was the high cost of PGx testing, followed by a lack of PGx education for healthcare providers or lack of clinical PGx experts. Physicians without clinical PGx experience or with indirect experience reported that the largest barrier to clinical implementation of PGx was the high cost of PGx testing, while physicians with clinical PGx experience pointed out that a lack of patients' education was the major concern, followed by a lack of PGx education for healthcare providers or lack of clinical PGx experts. The highest priority problem was reported to be a lack of actionable guidelines for drug selection and dosing using PGx. In conclusion, we should increase and expand extensive educational programs for healthcare providers and patients, and to develop and establish a clinical decision support systems for PGx-based personalized therapy in Korea.

Antiepileptic drug-induced severe cutaneous adverse reactions and HLA alleles: A report of five cases with lymphocyte activation test

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40–66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A,

Allopurinol-induced severe cutaneous adverse reactions: A report of three cases with the HLA-B*58:01 allele who underwent lymphocyte activation test

Allopurinol-induced severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome are reportedly associated with the HLA-B*58:01 genotype. Three patients who developed SCARs after allopurinol administration were subjected to HLA-B genotyping and lymphocyte activation test (LAT) to evaluate genetic risk and to detect the causative agent, respectively. All three patients given allopurinol to treat gout were diagnosed with DRESS syndrome. Symptom onset commenced 7-24 days after drug exposure; the patients took allopurinol (100–200 mg/d) for 2-30 days. HLA-B genotyping was performed using a polymerase chain reaction (PCR)-sequence-based typing (SBT) method. All patients had a single HLA-B*58:01 allele: HLA-B*13:02/*58:01 (a 63-year-old male), HLA-B*48:01/*58:01 (a 71-year-old female), and HLA-B*44:03/*58:01 (a 22-year-old male). Only the last patient yielded a positive LAT result, confirming that allopurinol was the causative agent. These findings suggest that patients with HLA-B*58:01 may develop SCARs upon allopurinol administration. Therefore, HLA-B genotyping could be helpful in preventing serious problems attributable to allopurinol treatment, although PCR-SBT HLA-B genotyping is time consuming. A simple genotyping test is required in practice. LAT may help to identify a causative agent.

Prediction and visualization of CYP2D6 genotype-based phenotype using clustering algorithms

This study focused on the role of cytochrome P450 2D6 (CYP2D6) genotypes to predict phenotypes in the metabolism of dextromethorphan. CYP2D6 genotypes and metabolic ratios (MRs) of dextromethorphan were determined in 201 Koreans. Unsupervised clustering algorithms, hierarchical and k-means clustering analysis, and color visualizations of CYP2D6 activity were performed on a subset of 130 subjects. A total of 23 different genotypes were identified, five of which were observed in one subject. Phenotype classifications were based on the means, medians, and standard deviations of the log MR values for each genotype. Color visualization was used to display the mean and median of each genotype as different color intensities. Cutoff values were determined using receiver operating characteristic curves from the k-means analysis, and the data were validated in the remaining subset of 71 subjects. Using the two highest silhouette values, the selected numbers of clusters were three (the best) and four. The findings from the two clustering algorithms were similar to those of other studies, classifying *5/*5 as a lowest activity group and genotypes containing duplicated alleles (i.e., CYP2D6*1/*2N) as a highest activity group. The validation of the k-means clustering results with data from the 71 subjects revealed relatively high concordance rates: 92.8% and 73.9% in three and four clusters, respectively. Additionally, color visualization allowed for rapid interpretation of results. Although the clustering approach to predict CYP2D6 phenotype from CYP2D6 genotype is not fully complete, it provides general information about the genotype to phenotype relationship, including rare genotypes with only one subject.

Brief introduction to current pharmacogenomics research tools

There is increasing interest in the application of personalized therapy to healthcare to increase the effectiveness of and reduce the adverse reactions to treatment. Pharmacogenomics is a core element in personalized therapy and pharmacogenomic research is a growing field. Understanding pharmacogenomic research tools enables better design, conduct, and analysis of pharmacogenomic studies, as well as interpretation of pharmacogenomic results. This review provides a general and brief introduction to pharmacogenomics research tools, including genotyping technology, web-based genome browsers, and software for haplotype analysis.

Effects of mirodenafil on the hemodynamics in hypertensive patients taking amlodipine

While phosphodiesterase type 5 inhibitors have been used for erectile dysfunction with acceptable safety profile, they can induce orthostatic hypotension in patients taking antihypertensive drugs with blood pressure lowering effect. This study evaluated the hemodynamic effects of 100 mg mirodenafil in hypertensive patients taking an amlodipine. Thirteen hypertensive patients who were taking 5 or 10 mg of amlodipine once daily participated in a randomized, double-blind, placebo-controlled, crossover study. A single oral dose of mirodenafil 100 mg or placebo was administered at 4.5 hour after administration of amlodipine. The maximal change in systolic and diastolic blood pressure (ΔmaxSBP and ΔmaxDBP) and pulse rate (ΔmaxPR) were compared between mirodenafil and placebo periods. Twelve patients completed this study and were included analysis. The values of ΔmaxPR in standing and supine position were significantly greater in the mirodenafil period (13.25±7.12 and 11.17±4.86 beats/minute) when compared to the placebo (8.50±4.72 and 6.58±3.90 beats/minute). The ΔmaxSBP and ΔmaxDBP in standing position appeared to be lower in the mirodenafil period, but they were not statistically different from those in the placebo period (ΔmaxSBP = -7.42±5.6 vs -4.42±5.37 mmHg and ΔmaxDBP = -7.17±5.72 vs -3.50±3.37 mmHg). Both ΔmaxSBP and ΔmaxDBP in standing and supine position were not significantly different between mirodenafil and placebo. This study demonstrated that mirodenafil exerted minimal hemodynamic effects in the patients taking amlodipine, that is unlikely associated with a clinically significant hypotensive event.

HLA-A*24:02/B*51:01 haplotype and lamotrigine-induced cutaneous adverse drug reactions in Koreans

Antiepileptic drugs (AEDs) have been known to induce cutaneous adverse drug reaction (cADR), ranging from a mild maculopapular eruption (MPE) to potentially life-threatening cADRs such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite studies examining mechanisms associated with human leukocyte antigen (HLA), the association between lamotrigine (LTG)-induced cADR and HLA alleles still has room to investigate. We investigated HLA-A,-B, and -C alleles in LTG-induced cADR. The medical records of four patients with LTG-induced cADR were retrospectively reviewed. All patients were treated with LTG for epilepsy. All recovered from cADR after stopping LTG treatment and receiving intensive care. HLA-A, -B, and -C genotyping was performed in all four patients using a PCR-sequence-based typing (SBT) method. Two patients had SJS, and the other two had MPE due to LTG. The range of latency to cADR after the initial LTG dose was 19–42 days. Two patients experienced cross-reactivity with other aromatic or new AEDs. Expression of the HLA-A*24:02/B*51:01 haplotype was detected in three (75%) patients with LTG-induced cADR. The other patient carried homozygous HLA-B*58:01 alleles. The results suggest that Korean individuals with the HLA-A*24:02/B*51:01 haplotype may be susceptible to LTG-induced cADR. Further investigations are necessary to confirm these findings.

Development and validation of a HPLC-UV method for 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in humans: providing in vivo evidence of CYP3A4-mediated CPHP formation

We developed a high-performance liquid chromatographic procedure for the determination of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in human. Chromatographic analysis was performed on a reverse-phase C₁₈ column with a mobile phase containing 50 mM potassium phosphate buffer/acetonitrile (75:25, vol/vol) using UV detection with a wavelength of 220 nm. The limits of detection for CPHP were 1 ng/ml in urine and the assay was linear over the concentration range of 2-500 ng/ml for urine. This analytical method was applied to measure CPHP in human. Nineteen healthy subjects were enrolled and all subjects received a single oral dose of 5 mg haloperidol following a treatment of placebo or itraconazole at 200 mg/day for 10 days in a randomized crossover manner. CPHP was detected in urine samples and average recovered amount of CPHP was 81.31 µg/24 hr in the placebo phase and it was significantly reduced to 30.34 µg/24 hr after itraconazole treatment. The finding provides in vivo evidence that CPHP is an in vivo metabolite of haloperidol in human and its formation is mediated by CYP3A4.

Population Pharmacokinetic Analysis of Piperacillin/Tazobactam in Korean Patients with Acute Infections

BACKGROUND: For more effective and safer usage of antibiotics, the dosing strategy should be individualized based on the patients’ characteristics, including race. The aim of this study was to investigate the population pharmacokinetic (PK) profiles of piperacillin and tazobactam in Korean patients with acute infections. MATERIALS AND METHODS: At least four consecutive 2/0.25 g or 4/0.5 g doses of piperacillin/tazobactam (TZP) were intravenously infused over 1 h every 8 h for patients with creatinine clearance (CL(cr)) ≤50 ml/min or CL(cr) >50 mL/min, respectively. Blood samples from 33 patients at a steady-state were taken pre-dose and at 0 min, 30 min, and 4-6 h after the fourth infusion. The population PK analysis was conducted using a non-linear mixed-effects method. A likelihood ratio test was used to select significant covariates, with significance levels of P <0.05 for selection and P <0.01 for elimination. RESULTS: Both piperacillin PK and tazobactam PK were well described by a two-compartment model with first-order elimination. Creatinine clearance and body weight, as covariates on clearance (CL) and volume of central compartment (V1), were selected among the covariates possibly affecting PK parameters of both drugs. CL was defined as CL = 2.9 + 4.03 × CL(cr)/47 for piperacillin and CL = 1.76 + 4.81 × CL(cr)/47 for tazobactam. V1 was defined as V1 = 19.5 × weight/60 for piperacillin and V1 = 22.6 × weight/60 for tazobactam. CONCLUSION: The PK profiles of TZP at a steady-state in Korean patients with acute infections were well described by a two-compartment model with first-order elimination. Both piperacillin and tazobactam clearances were significantly influenced by creatinine clearance.

Reversible Leukoencephlaopathy Caused by Doxifluridine in a Patient with Gastric Cancer

Doxifluridine neurotoxicity is more rare than 5-FU neurotoxicity. We report a case of leukoencephalopathy caused by long-term use of doxifluridine and which was resolved after discontinuation. A 37-year-old woman who had been on doxifluridine for 4 months after gastrectomy presented with dysarthria. Diffusion-weighted MRI imaging revealed multifocal hyperintense lesions in subcortical areas. Her symptoms disappeared after discontinuing doxifluridine, and lesions on follow-up MRI were resolved. These findings suggest that doxifluridine is a plausible cause of reversible leukoencephalopathy.

Low Serum Concentrations of Moxifloxacin, Prothionamide, and Cycloserine on Sputum Conversion in Multi-Drug Resistant TB

PURPOSE: Low serum concentrations of drugs used to treat multi-drug resistant tuberculosis (MDR-TB) have occasionally been associated with treatment failure. We determined the frequencies of low serum concentrations of anti-MDR-TB drugs, and assessed the effects of these concentrations on 2-month sputum conversion. MATERIALS AND METHODS: The serum levels of moxifloxacin (MF), prothionamide (PTH), and cycloserine (CS) were determined for 89 serum samples by high-pressure liquid chromatography-tandem mass spectrometry. RESULTS: Low serum concentrations of MF, PTH, and CS below the minimal levels of the normal ranges were 83.3% (20/24), 59.2% (29/49), and 71.2% (47/66), respectively. There were no significant differences between the 2-month sputum conversion group (n=25) and the 2-month sputum non-conversion group (n=4) in median drug concentrations (microg/mL) of MF (1.46 vs. 1.60), PTH (0.91 vs. 0.70), and CS (14.90 vs. 14.90). However, a poor compliance rate was significantly greater in the 2-month sputum non-conversion group (75.0%, 3/4) than in the 2-month sputum conversion group (0%, 0/25) (p=0.001). CONCLUSION: The frequency of low serum concentrations of anti-MDR-TB drugs was substantial and might not affect the 2-month sputum conversion rate. Larger prospective studies with timely sampling are needed to investigate the role of therapeutic drug monitoring in MDR-TB.

Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

The Vietnamese-Koreans, especially offspring between a Vietnamese mother and a Korean father constituted the highest proportion (64.2%) of total Kosian population according to a census in 2014. To evaluate genetic characteristics in the Vietnamese-Koreans, a total of 25 alleles from CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were genotyped using SNaPshot method with DNA samples of 127 Vietnamese-Koreans. The previous reports on the CYPs of Korean and Vietnamese populations were also analyzed for the comparative studies for the frequencies of CYP alleles. The statistical significances in allele and genotype frequencies among the ethnics were analyzed by Chi-square or Fisher's exact probability test. Although most of variants analyzed in 5 CYPs did not reach the statistically significant difference between the Vietnamese-Koreans and Vietnamese, some alleles were only found in Vietnamese-Koreans. Compared with Korean population, frequencies of CYP2D6*1 and CYP2D6*10B were statistically different from Vietnamese-Koreans (p<0.05). This is the first report to describe the CYP genotype profiles of Vietnamese-Koreans, which may provide important insight for the genotype based prediction of CYP activities of this admixture of Korean and Vietnamese.

Genetic Polymorphisms of the Carboxylesterase 1 (CES1) Gene in a Korean Population

Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyzes various exogenous compounds. Single nucleotide polymorphisms (SNPs) of CES1 may lead to inter-individual metabolic variability of its substrates. The allele and haplotype frequencies of known SNPs have been demonstrated to vary among ethnic groups. We analyzed genetic variations of CES1 in a Korean population. Direct sequencing of all exons and flanking regions of the CES1 gene was performed on samples obtained from 200 Koreans. We identified 41 SNPs. The most frequent SNPs was -914G>C (frequency: 99.5%), followed by 4256G>A (frequency: 65.8%), -75T>G (frequency: 59.3%). Haplotype analysis using the identified SNPs revealed fifteen haplotypes (> or =1% haplotype frequency) in our samples. The most frequent haplotype was Hap1 (frequency: 15.4%). Among the identified 41 SNPs, nine of which are novel variants and 14 SNPs were nonsynonymous variants. Using the functional predictive software PolyPhen-2, the G19V, E221G, and A270S variants were predicted to be most likely damaging to the function and structure of CES1. In-vitro analyses for two of these variants have been previously performed; however, functional evaluation of E221G (11657A>G, rs200707504) still needs to be conducted. Therefore, further studies are warranted to characterize the functional impact of E221G on CES1 activity.

The Development of Automated Bed-allocation Expert System in Clinical Research Ward

BACKGROUND: Demands for complicated and long-term administration clinical trials have been increased since investigators actively involved in early stage clinical trials including first-in-human (FIH) trials. Research wards in our clinical trial center were mainly used for phase 1 trials. In order to perform several clinical trials simultaneously during a short period with a minimum number of rooms, beds, and equipment, staffs have to spend a lot of time for efficient operation of limited numbers of facilities. In this study, automated bed-allocation system was developed for efficient scheduling of the research ward based on clinical trial condition and status like experts. METHODS: The system was developed based on clinical trial design, schedule, and the information on research bed and availability stored and updated in database (DB). Automatic assignment system was designed to find an optimal schedule according to the given information using expert rules and algorithms. The optimal solution can be visualized on Gantt chart using C# and Chart FX API. RESULTS: The system was developed to demonstrate the schedule on color chart. It turned out to be well-designed to find an optimal schedule for bed allocation. The system also allows automatic updating of the schedule and information in the DB. CONCLUSION: Automated bed-allocation system developed in this study could save time and improve the efficiency for using space and equipment in clinical trial center. The system can be also applied to similar works or tasks in other fields.

Retrospective Analysis of Adverse Reactions to Iodinated Contrast Media in Korean

BACKGROUND: This study was performed to evaluate the prevalence and risk factors on the adverse reactions caused by iodinated contrast media (CM) for computed tomography (CT) examination in a university hospital. METHODS: Clinical and demographic data among outpatients with CM use were collected at 0000 University Busanpaik Hospital in Busan, Korea between 2008 and 2010. Adverse reaction rate was calculated by the number of adverse reaction among total outpatients with CM use, which was stratified by seasons and sex. The association of risk factors on adverse reaction was investigated using logistic regression model. RESULTS: The total outpatients and events of administered CMs were 27,587 and 48,616, respectively. The administered CMs were iopromide, iohexol, iobitridol, and iodixanol. Adverse reactions occurred in 300 outpatients among the total outpatients (1.1 %). The number of outpatients administered CM more than twice were 8,348. Among them, outpatients who experienced adverse reaction(s) more than once and twice were 124 (1.5 %) and 26 (0.3 %), respectively. Adverse reaction rate was significantly different by sex(p=0.01). The other risk factors were cancer history (OR 2.57, 95 % CI 2.00-3.31) and previous CM administration (OR 1.89, 95 % CI 1.47-2.44). Urticaria was the most frequent symptoms. CONCLUSION: Total adverse reaction rate was 1.1 % with most common symptom in skin system. Related risk factors were female, cancer history, and previous CM administration. These results were similar to previous studies and will be contribute to clinical practice and future research especially in Koreans.

Retrospective Analysis of Adverse Reactions to Iodinated Contrast Media in Korean

BACKGROUND: This study was performed to evaluate the prevalence and risk factors on the adverse reactions caused by iodinated contrast media (CM) for computed tomography (CT) examination in a university hospital. METHODS: Clinical and demographic data among outpatients with CM use were collected at 0000 University Busanpaik Hospital in Busan, Korea between 2008 and 2010. Adverse reaction rate was calculated by the number of adverse reaction among total outpatients with CM use, which was stratified by seasons and sex. The association of risk factors on adverse reaction was investigated using logistic regression model. RESULTS: The total outpatients and events of administered CMs were 27,587 and 48,616, respectively. The administered CMs were iopromide, iohexol, iobitridol, and iodixanol. Adverse reactions occurred in 300 outpatients among the total outpatients (1.1 %). The number of outpatients administered CM more than twice were 8,348. Among them, outpatients who experienced adverse reaction(s) more than once and twice were 124 (1.5 %) and 26 (0.3 %), respectively. Adverse reaction rate was significantly different by sex(p=0.01). The other risk factors were cancer history (OR 2.57, 95 % CI 2.00-3.31) and previous CM administration (OR 1.89, 95 % CI 1.47-2.44). Urticaria was the most frequent symptoms. CONCLUSION: Total adverse reaction rate was 1.1 % with most common symptom in skin system. Related risk factors were female, cancer history, and previous CM administration. These results were similar to previous studies and will be contribute to clinical practice and future research especially in Koreans.

The Effect of CYP2D6/3A5 Genotypes on Plasma Concentrations of Haloperidol after Adjunctive Treatment of Aripiprazole

OBJECTIVES: To evaluate the drug interactions between aripiprazole and haloperidol, authors investigated plasma concentrations of those drugs by genotypes. METHOD: Fifty six patients with a confirmed Diagnostic and Statistical Manual of Mental Disorders 4th edition diagnosis of schizophrenia were enrolled in this eight-week, double blind, placebo-controlled study. Twenty-eight patients received adjunctive aripiprazole treatment and twenty-eight patients received placebo while being maintained on haloperidol treatment. Aripiprazole was dosed at 15 mg/day for the first 4 weeks, and then 30 mg for the next 4 weeks. The haloperidol dose remained fixed throughout the study. Plasma concentrations of haloperidol and aripiprazole were measured by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline, week 1, 2, 4 and 8. *1, *5, and *10 B alleles of CYP2D6 and *1 and *3 alleles of CYP3A5 were determined. The Student's T-test, Pearson's Chi-square test, Wilcoxon Rank Sum test and Logistic Regression analysis were used for data analysis. All tests were two-tailed and significance was defined as an alpha < 0.05. RESULTS: In the frequency of CYP2D6 genotype, *1/*10 B type was most frequent (36.5%) and *1/*1 (30.8%), *10B/*10B (17.3%) types followed. In the frequency of CYP3A5 genotype, *3/*3 type was found in 63.5% of subjects, and *1/*3 type and *1/*1 were 30.8% and 5.8% respectively. The plasma levels of haloperidol and its metabolites did not demonstrate significant time effects and time-group interactions after adjunctive treatment of aripiprazole. The genotypes of CYP2D6 and 3A5 did not affect the plasma concentration of haloperidol in this trial. No serious adverse event was found after adding aripiprazole to haloperidol. CONCLUSION: No significant drug interaction was found between haloperidol and aripiprazole. Genotypes of CYP2D6 and 3A5 did not affect the concentration of haloperidol after adding aripiprazole.

Association between Genetic Polymorphisms of CYP2D6 and Outcomes in Breast Cancer Patients with Tamoxifen Treatment

The aim of the study was to evaluate the association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. We evaluated the CYP2D6 genetic polymorphisms in 766 breast cancer patients. Among them, 110 patients whose samples were prospectively collected before surgery and treated with tamoxifen were included to evaluate the association between CYP2D6 and outcomes. The genotypes of CYP2D6 were categorized as extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) according to the activity score. The clinicopathologic features of 110 patients were not significantly different among the three groups except for the T-stage and nodal status. The high T-stage and axillary metastasis were more frequent in the PM group. While recurrence-free and overall survival in the PM group was poorer than the other groups, there was no significant difference between the EM and the IM group. The difference between the PM and the other groups on univariate analysis disappeared on multivariate analysis. These conflicting results suggest that the clinical value of CYP2D6 polymorphisms is still unclear and more large-sized and comprehensively designed trials are necessary.