Ho-Sook Kim - Academia.edu (original) (raw)

Papers by Ho-Sook Kim

Clinical Pharmacology & Therapeutics, 2020

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with a... more Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss‐of‐function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate‐induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single‐nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on‐clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018

BACKGROUND: Sophorae radix has been widely used for the treatment of diarrhea, inflammation, absc... more BACKGROUND: Sophorae radix has been widely used for the treatment of diarrhea, inflammation, abscess, dysentery, and fevers in Oriental countries. The major ingredients are known as prenylated flavonoids and may cause herb-drug interactions in human. In this study, the inhibition of CYP isoform activities by Sophorae radix extracts were evaluated in human liver microsomes. METHODS: Inhibition of the activities was evaluated by using CYP isoform selective probe substrates. Inhibition mechanism was determined by analysis of the inhibition after preincubation with inhibitors. RESULTS: The extracts inhibited CYP2C8, CYP2C9, CYP2C19, and CYP3A4 with IC50 values of 1.42, 13.6, 19.1, and 50 g/ml, respectively. Preincubation of human liver microsomes with the extracts in the presence of NADPH additionally inhibited CYP2B6 and CYP3A4 activities, indicating that the extracts may inhibit CYP2B6 and CYP3A4 by mechanism-based inactivation. Prenylated flavonoids played the role in the inhibition of CYP acitivities. CONCLUSION: The extracts of Sophorae radix was identified as an inhibitor for various CYP isoform activities and potential interaction with co-administered drugs should be carefully evaluated.

Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018

BACKGROUND: Somatic and hereditary germline mutations to increase the susceptibility to cancers h... more BACKGROUND: Somatic and hereditary germline mutations to increase the susceptibility to cancers have increased risk for developing cancer. Detection of these mutations in cancer patients can provide great benefits for diagnostics, prediction of prognosis and precision medicine. The objective of this study was to to develope and validated a custom Next Generation Sequencing (NGS) panel for analysis of known cancer-related biomarker. METHODS: Panel was designed a multiplex PCR targeting hotspot region of 20 genes (AKT1,

Translational and Clinical Pharmacology, 2020

Despite quantitative increases and qualitative advances in pharmacogenomics (PGx) research, the c... more 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 PGxbased 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.

Int. Journal of Clinical Pharmacology and Therapeutics, 2018

OBJECTIVE This study aimed at exploring the effects of metformin on the pharmacodynamics of vogli... more OBJECTIVE This study aimed at exploring the effects of metformin on the pharmacodynamics of voglibose, while investigating the pharmacodynamics between a fixed-dose combination (FDC) of voglibose/metformin and coadministered doses of voglibose and metformin tablets in healthy Korean subjects. MATERIALS AND METHODS A randomized, open-label, 2×3×3 crossover study with a 9-day washout period was conducted in 30 healthy subjects. All subjects received orally administered voglibose alone, individual voglibose and metformin tablets, or FDC 3 times daily for 5 days. Oral sucrose was administered on day -1 (pretreatment) and at 10 minutes after the morning dose of the study drug on day 5 of each period. Plasma glucose and serum insulin were measured over the course of 2 hours following sucrose loading. RESULTS 21 subjects completed the study. The geometric mean ratios (GMR) of ΔCmax and the AUC of glucose for voglibose plus metformin vs. voglibose alone were 0.995 (90% CI, 0.800 - 1.237) and 0.969 (90% CI, 0.949 - 0.990), respectively; the GMRs for individual tablets vs. FDC were 1.118 (90% CI, 0.930 - 1.344) and 1.010 (90% CI, 0.974 - 1.048), respectively. A relatively smaller number of subjects experienced adverse events when receiving voglibose alone compared to those administered FDC or metformin and voglibose. There were no significant differences in adverse events between individual voglibose and metformin tablets and FDC. CONCLUSION Coadministered metformin did not have statistically or clinically significant effects on the pharmacodynamics of voglibose in healthy subjects. Glucose levels following sucrose loading seem not to be clinically different between FDC and individual tablets of voglibose and metformin. .

Annals of Oncology, 2012

3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinote... more 3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 (*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA group. The MTD was estimated as 300 mg/m2/2-week for the 1 DA group with 2 DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, respectively (P=0.017). Of the 43 pts, five pts showed AUClast, SN38 that exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete responses and 23 partial responses. Median progression-free and overall survival was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), respectively. Grade 3 or 4 toxicity during all treatment cycles included neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of irinotecan was 330, 270, 150 mg/m2/2-week for pts with 0, 1, 2 DA based on pharmacokinetic analysis. [Table: see text]

European Heart Journal - Cardiovascular Pharmacotherapy, 2019

Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigatio... more Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. Methods and results We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10−54; CES1 G143E, P = 1.3 × 10−16; CYP2C19*17, P = 9.5 × 10−10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10−4; CYP2B6 516 G > T,...

Int. Journal of Clinical Pharmacology and Therapeutics, 2019

OBJECTIVE The objective of this study was to explore a pharmacogenomic information-based enrichme... more OBJECTIVE The objective of this study was to explore a pharmacogenomic information-based enrichment study design for reducing the sample size in bioequivalence (BE) studies using tolterodine and CYP2D6 genotypes. MATERIALS AND METHODS A BE study of tolterodine was performed in a randomized, open-label, 2×2 cross-over design. A two one-sided test (TOST) was executed for pharmacokinetic (PK) parameters of tolterodine, and their geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were estimated. The coefficient of variation (CV) was calculated for each cytochrome P450 (CYP) 2D6 genotype group, and the sample size required to meet the power of an equivalence test was estimated, based on TOST in genotype stratified groups as well as in a conventional group. Replicated simulation datasets of PK parameters for each genotype group were generated using bootstrap resampling technique. RESULTS The CVs of PK parameters in the conventional dataset were much greater than those in the genotype-based stratified groups. While up to 70 subjects were required for statistical power based on the CV of the area under the concentration-time curve (AUCt) observed in the conventional dataset, only 26 - 44 subjects in extensive metabolizers (EMs) and poor metabolizers (PMs), respectively, were required for the CYP2D6 genotype groups. The 90% CIs for GMR in all simulated datasets appeared to meet the BE criterion (0.8 - 1.25). CONCLUSION This exploration demonstrated that a drug-metabolizing enzyme genotype-based enrichment strategy can be implemented to minimize the sample size in BE studies of drugs that have high PK variability due to polymorphic metabolizing enzyme(s).

American heart journal, 2018

The P2Y receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, p... more The P2Y receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candi...

Journal of the Korean Neurological Association, 2016

Doxifluridine neurotoxicity is more rare than 5-FU neurotoxicity. We report a case of leukoenceph... more 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.

Translational and Clinical Pharmacology, 2016

There is increasing interest in the application of personalized therapy to healthcare to increase... more 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. This review will introduce key tools for pharmacogenomic researches including widely used genotyping technologies, simple and free softwares for haplotype construction, and web resources. We hope this information will increase the understanding and knowledge of pharmacogenomics and its interpretation. Genotyping Methods Recent advances in genotyping technology, such as gene chips and next generation sequencing (NGS) can now accommo

Genetics in medicine : official journal of the American College of Medical Genetics, Aug 23, 2015

We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ... more We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.78...

British journal of clinical pharmacology, 2015

The primary objective of this study was to evaluate pharmacokinetic and pharmacodynamic interacti... more The primary objective of this study was to evaluate pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes. In a randomized, 3-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg), or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4'-trans-hydroxycilostazol), and ADP-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. The area under the plasma concentration-time curve (AUC) of clopidogrel active thiol metabolite was highest in CYP2C19 extensive metabolizer (EM) and lowest in poor metabolizers (PM). Cilostazol decreased thiol metabolite AUC 29% in CYP3A5*1/*3 (Geometric mean ratio (GMR), 0.71; 90% CI, 0.58-0.86; p = 0.020) but not in CYP3A5*3/*3 (GMR, 0.93; 90% CI, 0.80-1.10; p = 0.446). Known CYP2C1...

AIM: The objective of this study was to validate the previous reported algorism of steady-state w... more AIM: The objective of this study was to validate the previous reported algorism of steady-state warfarin dose in Korean patients from the larger data set and further develop the predictive model for the randomized clinical trial of genotype-guided personalized warfarin pharmacotherapy. METHODS: Genotyping for CYP2C9*3, *13, *14 and VKORC1 -1639G>A were performed in Korean 560 patients receiving warfarin maintenance therapy for mechanical heart valve replacement(MHVR), atrial fibrillation, stroke, valvular heat disease or pulmonary embolism Multivariate linear regression was performed to model the relationships of warfarin dose with other variables and to develop a warfarin dosing algorithm. RESULTS: Previous developed model of steady state warfarin dose estimation in Korean patients with MHVR was over-predicted in other indications due to co-administration of more frequent warfarin-interacting drug. The model for steady-state warfarin dose was newly developed including the variab...

CYP2C9 single nucleotide polymorphisms (SNPs) are important in safe and effective oral anticoagul... more CYP2C9 single nucleotide polymorphisms (SNPs) are important in safe and effective oral anticoagulation with warfarin use.The objectives of this study were to determine the distribution of CYP2C9 variants in Koreans and investigate their association with warfarin dose requirements in patients who received mechanical heart valve replacements (MHVRs). All 9 exons, intron–exon junction, and promoter region of CYP2C9 were amplified and the amplified fragments were directly sequenced in 50 healthy normal Koreans. Additional direct DNA sequencing of the CYP2C9 gene was conducted in 36 of the 267 MHVR patients who required low maintenance warfarin doses without carrying CYP2C9*3 and VKORC1 1173T mutations. The effects of CYP2C9 genetics on warfarin maintenance dose was assessed in 267 MHVR patients. Thirty-nine SNPs including seven previously unidentified SNPs were identified in 50 Koreans by direct DNA sequencing. One of the CYP2C9 haplotypes exhibited an association with warfarin low dose...

Int. Journal of Clinical Pharmacology and Therapeutics, 2014

The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of m... more The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of metformin. A randomized, open-label, two-way crossover study with a 7-day washout period was conducted. All subjects were given an oral dose of metformin with or without voglibose 3 x daily for 7 days. Plasma concentrations of metformin on day 7 were measured using high performance liquid chromatography (HPLC) with UV detection for pharmacokinetic assessment Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. 22 subjects completed the study. The geometric mean ratios for Css,max of metformin (metformin plus voglibose vs. metformin only) were 0.98 (90% CI, 0.92 - 1.05; p > 0.05) and for AUC-tau, the ratio was 0.99 (90% CI, 0.92 - 1.06; p > 0.05). There were no significant differences in adverse drug reactions between metformin with and without voglibose. However, the incidence of adverse events was higher in period 1 than in period 2 (16 cases vs. 1 case, p < 0.001). Co-administration of metformin and voglibose had no statistically or clinically significant effects on the pharmacokinetics of metformin in healthy subjects. The pharmacodynamic interaction study to evaluate the effect of metformin on the pharmacodynamics of voglibose is in progress.

International journal of clinical pharmacology and therapeutics, 2015

The aim of this study was to compare the pharmacokinetic characteristics of metformin between a f... more The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5 - 111.0) and 107.1 (100.1 - 114.7), respectively. In total, 7 adverse drug reactions ...

International Journal of Molecular Sciences, 2014

There has been a wide range of inter-individual variations in platelet responses to clopidogrel. ... more There has been a wide range of inter-individual variations in platelet responses to clopidogrel. The variations in response to clopidogrel can be driven by genetic polymorphisms involved in the pathway of absorption, distribution, metabolism, excretion, and the target receptor P2Y12. A set of genetic variants known for causing variations in clopidogrel responses was selected, which included CYP2C19*2, *3, *17, CYP2B6*4, *6, *9, CYP3A4*18, CYP3A5*3, MDR1 2677G > T/A, 3435C > T, and P2Y12 H2 (742T > C). The simultaneous detection of these 10 variants was developed by using a multiplex PCR and single-base extension (MSSE) methodology. The newly developed genotyping test was confirmed by direct DNA sequencing in the representative positive control samples and validated in an extended set of 100 healthy Korean subjects. Genotyping results from the developed MSSE exhibited a perfect concordance with the direct DNA sequencing data and all of variants tested in 100 healthy Korean subjects were in agreement with Hardy-Weinberg equilibrium (p > 0.05). The present molecular diagnostic studies provide

Oncology, Jan 21, 2014

Purpose: A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patie... more Purpose: A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patients with metastatic colorectal cancer receiving first-line FOLFIRI chemotherapy. Methods: Patients were genotyped for UGT1A1 and stratified according to the number of defective alleles (DA; *28 and *6). The irinotecan dose was escalated with a fixed dose of 5-fluorouracil and leucovorin in a standard 3 + 3 design. Results: In 43 enrolled patients, the maximum tolerated dose (MTD) was 300 mg/m(2) for the 1 DA group, while the MTD was not reached for the 0 DA group with 1 dose-limiting toxicity (DLT) at 330 mg/m(2) and for the 2 DA group with 0 DLT at 150 mg/m(2). Because of the risk of being exposed to unsafe doses, the trial was terminated before the MTD was reached in the 0 DA and 2 DA groups. The recommended doses were 300 (0 DA), 270 (1 DA) and 150 (0 DA) mg/m(2). The 2 DA group displayed 27% lower SN-38 exposure levels relative to the 0 and 1 DA groups (95% CI, 0.47-1.15). Conclusion...

International journal of clinical pharmacology and therapeutics, 2015

The aim of this study was to compare pharmacokinetic characteristics of fixed-dose combination (F... more The aim of this study was to compare pharmacokinetic characteristics of fixed-dose combination (FDC) of two different salt form of amlodipine, amlodipine adipate/valsartan and amlodipine besylate/ valsartan, in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 14-day wash-out period was conducted. Plasma samples were collected for up to 144 hours for amlodipine and 24 hours for valsartan. Plasma concentrations of amlodipine and valsartan were analyzed using a validated ultra-performance liquid chromatography tandem mass-spectrometry. A non-compartmental method was used to calculate pharmacokinetic parameters. Vital signs and adverse events were monitored and physical examinations, laboratory tests, and electrocardiograms were conducted to evaluate safety. 44 subjects completed the study. The 90% CIs for the geometric mean ratio of Cmax and the AUC0-t were 93.5 - 100.4% and 93.2 - 98.3% for amlodip...

Clinical Pharmacology & Therapeutics, 2020

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with a... more Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss‐of‐function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate‐induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single‐nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on‐clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018

BACKGROUND: Sophorae radix has been widely used for the treatment of diarrhea, inflammation, absc... more BACKGROUND: Sophorae radix has been widely used for the treatment of diarrhea, inflammation, abscess, dysentery, and fevers in Oriental countries. The major ingredients are known as prenylated flavonoids and may cause herb-drug interactions in human. In this study, the inhibition of CYP isoform activities by Sophorae radix extracts were evaluated in human liver microsomes. METHODS: Inhibition of the activities was evaluated by using CYP isoform selective probe substrates. Inhibition mechanism was determined by analysis of the inhibition after preincubation with inhibitors. RESULTS: The extracts inhibited CYP2C8, CYP2C9, CYP2C19, and CYP3A4 with IC50 values of 1.42, 13.6, 19.1, and 50 g/ml, respectively. Preincubation of human liver microsomes with the extracts in the presence of NADPH additionally inhibited CYP2B6 and CYP3A4 activities, indicating that the extracts may inhibit CYP2B6 and CYP3A4 by mechanism-based inactivation. Prenylated flavonoids played the role in the inhibition of CYP acitivities. CONCLUSION: The extracts of Sophorae radix was identified as an inhibitor for various CYP isoform activities and potential interaction with co-administered drugs should be carefully evaluated.

Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018

BACKGROUND: Somatic and hereditary germline mutations to increase the susceptibility to cancers h... more BACKGROUND: Somatic and hereditary germline mutations to increase the susceptibility to cancers have increased risk for developing cancer. Detection of these mutations in cancer patients can provide great benefits for diagnostics, prediction of prognosis and precision medicine. The objective of this study was to to develope and validated a custom Next Generation Sequencing (NGS) panel for analysis of known cancer-related biomarker. METHODS: Panel was designed a multiplex PCR targeting hotspot region of 20 genes (AKT1,

Translational and Clinical Pharmacology, 2020

Despite quantitative increases and qualitative advances in pharmacogenomics (PGx) research, the c... more 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 PGxbased 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.

Int. Journal of Clinical Pharmacology and Therapeutics, 2018

OBJECTIVE This study aimed at exploring the effects of metformin on the pharmacodynamics of vogli... more OBJECTIVE This study aimed at exploring the effects of metformin on the pharmacodynamics of voglibose, while investigating the pharmacodynamics between a fixed-dose combination (FDC) of voglibose/metformin and coadministered doses of voglibose and metformin tablets in healthy Korean subjects. MATERIALS AND METHODS A randomized, open-label, 2×3×3 crossover study with a 9-day washout period was conducted in 30 healthy subjects. All subjects received orally administered voglibose alone, individual voglibose and metformin tablets, or FDC 3 times daily for 5 days. Oral sucrose was administered on day -1 (pretreatment) and at 10 minutes after the morning dose of the study drug on day 5 of each period. Plasma glucose and serum insulin were measured over the course of 2 hours following sucrose loading. RESULTS 21 subjects completed the study. The geometric mean ratios (GMR) of ΔCmax and the AUC of glucose for voglibose plus metformin vs. voglibose alone were 0.995 (90% CI, 0.800 - 1.237) and 0.969 (90% CI, 0.949 - 0.990), respectively; the GMRs for individual tablets vs. FDC were 1.118 (90% CI, 0.930 - 1.344) and 1.010 (90% CI, 0.974 - 1.048), respectively. A relatively smaller number of subjects experienced adverse events when receiving voglibose alone compared to those administered FDC or metformin and voglibose. There were no significant differences in adverse events between individual voglibose and metformin tablets and FDC. CONCLUSION Coadministered metformin did not have statistically or clinically significant effects on the pharmacodynamics of voglibose in healthy subjects. Glucose levels following sucrose loading seem not to be clinically different between FDC and individual tablets of voglibose and metformin. .

Annals of Oncology, 2012

3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinote... more 3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 (*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA group. The MTD was estimated as 300 mg/m2/2-week for the 1 DA group with 2 DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, respectively (P=0.017). Of the 43 pts, five pts showed AUClast, SN38 that exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete responses and 23 partial responses. Median progression-free and overall survival was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), respectively. Grade 3 or 4 toxicity during all treatment cycles included neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of irinotecan was 330, 270, 150 mg/m2/2-week for pts with 0, 1, 2 DA based on pharmacokinetic analysis. [Table: see text]

European Heart Journal - Cardiovascular Pharmacotherapy, 2019

Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigatio... more Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. Methods and results We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10−54; CES1 G143E, P = 1.3 × 10−16; CYP2C19*17, P = 9.5 × 10−10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10−4; CYP2B6 516 G > T,...

Int. Journal of Clinical Pharmacology and Therapeutics, 2019

OBJECTIVE The objective of this study was to explore a pharmacogenomic information-based enrichme... more OBJECTIVE The objective of this study was to explore a pharmacogenomic information-based enrichment study design for reducing the sample size in bioequivalence (BE) studies using tolterodine and CYP2D6 genotypes. MATERIALS AND METHODS A BE study of tolterodine was performed in a randomized, open-label, 2×2 cross-over design. A two one-sided test (TOST) was executed for pharmacokinetic (PK) parameters of tolterodine, and their geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were estimated. The coefficient of variation (CV) was calculated for each cytochrome P450 (CYP) 2D6 genotype group, and the sample size required to meet the power of an equivalence test was estimated, based on TOST in genotype stratified groups as well as in a conventional group. Replicated simulation datasets of PK parameters for each genotype group were generated using bootstrap resampling technique. RESULTS The CVs of PK parameters in the conventional dataset were much greater than those in the genotype-based stratified groups. While up to 70 subjects were required for statistical power based on the CV of the area under the concentration-time curve (AUCt) observed in the conventional dataset, only 26 - 44 subjects in extensive metabolizers (EMs) and poor metabolizers (PMs), respectively, were required for the CYP2D6 genotype groups. The 90% CIs for GMR in all simulated datasets appeared to meet the BE criterion (0.8 - 1.25). CONCLUSION This exploration demonstrated that a drug-metabolizing enzyme genotype-based enrichment strategy can be implemented to minimize the sample size in BE studies of drugs that have high PK variability due to polymorphic metabolizing enzyme(s).

American heart journal, 2018

The P2Y receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, p... more The P2Y receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candi...

Journal of the Korean Neurological Association, 2016

Doxifluridine neurotoxicity is more rare than 5-FU neurotoxicity. We report a case of leukoenceph... more 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.

Translational and Clinical Pharmacology, 2016

There is increasing interest in the application of personalized therapy to healthcare to increase... more 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. This review will introduce key tools for pharmacogenomic researches including widely used genotyping technologies, simple and free softwares for haplotype construction, and web resources. We hope this information will increase the understanding and knowledge of pharmacogenomics and its interpretation. Genotyping Methods Recent advances in genotyping technology, such as gene chips and next generation sequencing (NGS) can now accommo

Genetics in medicine : official journal of the American College of Medical Genetics, Aug 23, 2015

We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ... more We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.78...

British journal of clinical pharmacology, 2015

The primary objective of this study was to evaluate pharmacokinetic and pharmacodynamic interacti... more The primary objective of this study was to evaluate pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes. In a randomized, 3-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg), or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4'-trans-hydroxycilostazol), and ADP-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. The area under the plasma concentration-time curve (AUC) of clopidogrel active thiol metabolite was highest in CYP2C19 extensive metabolizer (EM) and lowest in poor metabolizers (PM). Cilostazol decreased thiol metabolite AUC 29% in CYP3A5*1/*3 (Geometric mean ratio (GMR), 0.71; 90% CI, 0.58-0.86; p = 0.020) but not in CYP3A5*3/*3 (GMR, 0.93; 90% CI, 0.80-1.10; p = 0.446). Known CYP2C1...

AIM: The objective of this study was to validate the previous reported algorism of steady-state w... more AIM: The objective of this study was to validate the previous reported algorism of steady-state warfarin dose in Korean patients from the larger data set and further develop the predictive model for the randomized clinical trial of genotype-guided personalized warfarin pharmacotherapy. METHODS: Genotyping for CYP2C9*3, *13, *14 and VKORC1 -1639G>A were performed in Korean 560 patients receiving warfarin maintenance therapy for mechanical heart valve replacement(MHVR), atrial fibrillation, stroke, valvular heat disease or pulmonary embolism Multivariate linear regression was performed to model the relationships of warfarin dose with other variables and to develop a warfarin dosing algorithm. RESULTS: Previous developed model of steady state warfarin dose estimation in Korean patients with MHVR was over-predicted in other indications due to co-administration of more frequent warfarin-interacting drug. The model for steady-state warfarin dose was newly developed including the variab...

CYP2C9 single nucleotide polymorphisms (SNPs) are important in safe and effective oral anticoagul... more CYP2C9 single nucleotide polymorphisms (SNPs) are important in safe and effective oral anticoagulation with warfarin use.The objectives of this study were to determine the distribution of CYP2C9 variants in Koreans and investigate their association with warfarin dose requirements in patients who received mechanical heart valve replacements (MHVRs). All 9 exons, intron–exon junction, and promoter region of CYP2C9 were amplified and the amplified fragments were directly sequenced in 50 healthy normal Koreans. Additional direct DNA sequencing of the CYP2C9 gene was conducted in 36 of the 267 MHVR patients who required low maintenance warfarin doses without carrying CYP2C9*3 and VKORC1 1173T mutations. The effects of CYP2C9 genetics on warfarin maintenance dose was assessed in 267 MHVR patients. Thirty-nine SNPs including seven previously unidentified SNPs were identified in 50 Koreans by direct DNA sequencing. One of the CYP2C9 haplotypes exhibited an association with warfarin low dose...

Int. Journal of Clinical Pharmacology and Therapeutics, 2014

The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of m... more The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of metformin. A randomized, open-label, two-way crossover study with a 7-day washout period was conducted. All subjects were given an oral dose of metformin with or without voglibose 3 x daily for 7 days. Plasma concentrations of metformin on day 7 were measured using high performance liquid chromatography (HPLC) with UV detection for pharmacokinetic assessment Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. 22 subjects completed the study. The geometric mean ratios for Css,max of metformin (metformin plus voglibose vs. metformin only) were 0.98 (90% CI, 0.92 - 1.05; p > 0.05) and for AUC-tau, the ratio was 0.99 (90% CI, 0.92 - 1.06; p > 0.05). There were no significant differences in adverse drug reactions between metformin with and without voglibose. However, the incidence of adverse events was higher in period 1 than in period 2 (16 cases vs. 1 case, p < 0.001). Co-administration of metformin and voglibose had no statistically or clinically significant effects on the pharmacokinetics of metformin in healthy subjects. The pharmacodynamic interaction study to evaluate the effect of metformin on the pharmacodynamics of voglibose is in progress.

International journal of clinical pharmacology and therapeutics, 2015

The aim of this study was to compare the pharmacokinetic characteristics of metformin between a f... more The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5 - 111.0) and 107.1 (100.1 - 114.7), respectively. In total, 7 adverse drug reactions ...

International Journal of Molecular Sciences, 2014

There has been a wide range of inter-individual variations in platelet responses to clopidogrel. ... more There has been a wide range of inter-individual variations in platelet responses to clopidogrel. The variations in response to clopidogrel can be driven by genetic polymorphisms involved in the pathway of absorption, distribution, metabolism, excretion, and the target receptor P2Y12. A set of genetic variants known for causing variations in clopidogrel responses was selected, which included CYP2C19*2, *3, *17, CYP2B6*4, *6, *9, CYP3A4*18, CYP3A5*3, MDR1 2677G > T/A, 3435C > T, and P2Y12 H2 (742T > C). The simultaneous detection of these 10 variants was developed by using a multiplex PCR and single-base extension (MSSE) methodology. The newly developed genotyping test was confirmed by direct DNA sequencing in the representative positive control samples and validated in an extended set of 100 healthy Korean subjects. Genotyping results from the developed MSSE exhibited a perfect concordance with the direct DNA sequencing data and all of variants tested in 100 healthy Korean subjects were in agreement with Hardy-Weinberg equilibrium (p > 0.05). The present molecular diagnostic studies provide

Oncology, Jan 21, 2014

Purpose: A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patie... more Purpose: A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patients with metastatic colorectal cancer receiving first-line FOLFIRI chemotherapy. Methods: Patients were genotyped for UGT1A1 and stratified according to the number of defective alleles (DA; *28 and *6). The irinotecan dose was escalated with a fixed dose of 5-fluorouracil and leucovorin in a standard 3 + 3 design. Results: In 43 enrolled patients, the maximum tolerated dose (MTD) was 300 mg/m(2) for the 1 DA group, while the MTD was not reached for the 0 DA group with 1 dose-limiting toxicity (DLT) at 330 mg/m(2) and for the 2 DA group with 0 DLT at 150 mg/m(2). Because of the risk of being exposed to unsafe doses, the trial was terminated before the MTD was reached in the 0 DA and 2 DA groups. The recommended doses were 300 (0 DA), 270 (1 DA) and 150 (0 DA) mg/m(2). The 2 DA group displayed 27% lower SN-38 exposure levels relative to the 0 and 1 DA groups (95% CI, 0.47-1.15). Conclusion...

International journal of clinical pharmacology and therapeutics, 2015

The aim of this study was to compare pharmacokinetic characteristics of fixed-dose combination (F... more The aim of this study was to compare pharmacokinetic characteristics of fixed-dose combination (FDC) of two different salt form of amlodipine, amlodipine adipate/valsartan and amlodipine besylate/ valsartan, in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 14-day wash-out period was conducted. Plasma samples were collected for up to 144 hours for amlodipine and 24 hours for valsartan. Plasma concentrations of amlodipine and valsartan were analyzed using a validated ultra-performance liquid chromatography tandem mass-spectrometry. A non-compartmental method was used to calculate pharmacokinetic parameters. Vital signs and adverse events were monitored and physical examinations, laboratory tests, and electrocardiograms were conducted to evaluate safety. 44 subjects completed the study. The 90% CIs for the geometric mean ratio of Cmax and the AUC0-t were 93.5 - 100.4% and 93.2 - 98.3% for amlodip...