Antioxidant Efficacy of Hwangryunhaedok-tang through Nrf2 and AMPK Signaling Pathway against Neurological Disorders In Vivo and In Vitro.

Alzheimer's disease (AD) is a representative cause of dementia and is caused by neuronal loss, leading to the accumulation of aberrant neuritic plaques and the formation of neurofibrillary tangles. Oxidative stress is involved in the impaired clearance of amyloid beta (Aß), and Aß-induced oxidative stress causes AD by inducing the formation of neurofibrillary tangles. Hwangryunhaedok-tang (HHT, Kracie K-09®), a traditional herbal medicine prescription, has shown therapeutic effects on various diseases. However, the studies of HHT as a potential treatment for AD are insufficient. Therefore, our study identified the neurological effects and mechanisms of HHT and its key bioactive compounds against Alzheimer's disease in vivo and in vitro. In a 5xFAD mouse model, our study confirmed that HHT attenuated cognitive impairments in the Morris water maze (MWM) test and passive avoidance (PA) test. In addition, the prevention of neuron impairment, reduction in the protein levels of Aß, and inhibition of cell apoptosis were confirmed with brain tissue staining. In HT-22 cells, HHT attenuates tBHP-induced cytotoxicity, ROS generation, and mitochondrial dysfunction. It was verified that HHT exerts a neuroprotective effect by activating signaling pathways interacting with Nrf2, such as MAPK/ERK, PI3K/Akt, and LKB1/AMPK. Among the components, baicalein, a bioavailable compound of HHT, exhibited neuroprotective properties and activated the Akt, AMPK, and Nrf2/HO-1 pathways. Our findings indicate a mechanism for HHT and its major bioavailable compounds to treat and prevent AD and suggest its potential.

Pharmacokinetics and safety of evogliptin in hepatically impaired patients.

AIMS: Evogliptin is a potent and selective dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes mellitus. Since evogliptin is mainly eliminated through hepatic metabolism, we investigated the pharmacokinetics (PKs) and safety characteristics of evogliptin in Korean patients with mild or moderate hepatic impairment. METHODS: An open-label, parallel-group study was conducted in patients with mild or moderate hepatic impairment and healthy control subjects matched to each patient for sex, age and body mass index. A single dose (5 mg) of evogliptin was administered orally, and serial blood samples were collected over 120 h to assess the PK profile of evogliptin and its main metabolites (M7 and M8). RESULTS: Patients with mild hepatic impairment and their matched healthy controls showed similar maximum concentration (Cmax ) and area under the concentration-time curve values from 0 to 120 h (AUClast ); the geometric mean ratio (GMR) and 90% confidence interval (CI) were 1.04 (0.80, 1.35) and 1.01 (0.90, 1.14), respectively. Exposure to evogliptin (Cmax and AUClast ) was increased by about 40% in patients with moderate hepatic impairment-the GMR and 90% CI were 1.37 (1.09, 1.72) and 1.44 (1.18, 1.75), respectively. The metabolic ratios of M7 and M8 were lower in patients with moderate hepatic impairment than in matched healthy controls. Evogliptin was well tolerated by both patients and healthy subjects. CONCLUSION: Although evogliptin exposure was increased in patients with moderate hepatic impairment, the increase is unlikely to affect safety and efficacy adversely, and no dose adjustment is warranted.

Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers.

AIM: The organic cation transporter 1 (OCT1) plays a key role in the cellular transport of metformin and its subsequent glucose-lowering effect. A recent non-clinical study reported that metformin uptake into hepatocytes is regulated via OCT1, and that uptake was strongly inhibited by verapamil. Therefore, we investigated the effects of verapamil co-administration on the pharmacokinetics and pharmacodynamics of metformin in humans. METHODS: We evaluated the pharmacokinetics and the anti-hyperglycaemic effects of metformin using an oral glucose tolerance test (OGTT) in 12 healthy participants, before (day 1) and after metformin treatment (day 2), and again on days 15 and 16 after co-administration with verapamil. RESULTS: Verapamil inhibited the ability of metformin to reduce maximum blood glucose concentrations (ΔGmax ) by 62.5% (P = 0.008) and decreased the area under the glucose concentration-time curve (ΔAUCgluc ) by 238% (P = 0.015). However, verapamil did not significantly alter the Cmax and the AUC of metformin, nor its renal clearance. CONCLUSIONS: Our results suggest that verapamil remarkably decreases the glucose-lowering effect of metformin, possibly by acting as a competitive inhibitor of OCT1.

The Association between Serum Lipid Levels and Tinnitus Prevalence and Severity in Korean Elderly: A Nationwide Population-Based Cross-Sectional Study.

PURPOSE: We aimed to investigate the association between serum lipid level and tinnitus risk in Korean older adults. MATERIALS AND METHODS: This study used data from the 2016-2018 Korea National Health and Nutrition Examination Survey. Overall, 6021 subjects aged ≥60 years were included. Hypertriglyceridemia was defined as a serum triglyceride level of ≥200 mg/dL. The high-risk threshold of the total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio was defined as above 5.0. The presence of tinnitus was assessed via health interviews. Tinnitus severity was classified as "not annoying," "irritating," and "severely annoying and causing sleep problems." Multivariate logistic regression analysis was performed to examine the association between serum lipid level and tinnitus risk. RESULTS: The odds ratio (OR) of tinnitus was 1.27-times higher in the group with hypertriglyceridemia than in the group without hypertriglyceridemia after adjusting for age, sex, hypertension, diabetes, dyslipidemia, anemia, current smoking, obesity, noise exposure, stress cognition, and depressive mood or anxiety [95% confidence interval (CI) 1.04-1.56, p=0.022]. The OR of tinnitus was 1.21-times higher in the group with a high TC/HDL-C ratio than in the group without a high TC/HDL-C ratio after adjusting for the same variables as above (95% CI 1.02-1.44, p=0.025). CONCLUSION: This study revealed that hypertriglyceridemia and high TC/HDL-C ratio were significantly associated with an increased OR of tinnitus in Korean older adults.

Population pharmacokinetic-pharmacodynamic modeling of clopidogrel for dose regimen optimization based on CYP2C19 phenotypes: A proof of concept study.

Clopidogrel is an antiplatelet drug used to reduce the risk of acute coronary syndrome and stroke. It is converted by CYP2C19 to its active metabolite; therefore, poor metabolizers (PMs) of CYP2C19 exhibit diminished antiplatelet effects. Herein, we conducted a proof-of-concept study for using population pharmacokinetic-pharmacodynamic (PK-PD) modeling to recommend a personalized clopidogrel dosing regimen for individuals with varying CYP2C19 phenotypes and baseline P2Y12 reaction unit (PRU) levels. Data from a prospective phase I clinical trial involving 36 healthy male participants were used to develop the population PK-PD model predicting the concentrations of clopidogrel, clopidogrel H4, and clopidogrel carboxylic acid, and linking clopidogrel H4 concentrations to changes in PRU levels. A two-compartment model effectively described the PKs of both clopidogrel and clopidogrel carboxylic acid, and a one-compartment model of those of clopidogrel H4. The CYP2C19 phenotype was identified as a significant covariate influencing the metabolic conversion of the parent drug to its metabolites. A PD submodel of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PMs require three to four times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20th percentile of baseline PRU levels were shown to require 2.5-3 times higher doses than those in the bottom 20th percentile. We successfully developed a population PK-PD model for clopidogrel considering the impact of CYP2C19 phenotypes and baseline PRU levels. Further studies are necessary to confirm actual dosing recommendations for clopidogrel.

Pharmacokinetic Modeling of Bepotastine for Determination of Optimal Dosage Regimen in Pediatric Patients with Allergic Rhinitis or Urticaria.

Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on population pharmacokinetic (popPK) and physiologically based pharmacokinetic (PBPK) models using data from two previous trials. A popPK model was built using NONMEM software. A one-compartment model with first-order absorption and absorption lag time described our data well, with body weight incorporated as the only covariate. A PBPK model was developed using PK-Sim software version 10, and the model well predicted the drug concentrations obtained from pediatric patients. Furthermore, the final PBPK model showed good concordance with the known properties of bepotastine. Appropriate pediatric doses for different weight and age groups were proposed based on the simulations. Discrepancies in recommended doses from the two models were likely due to the incorporation of age-dependent physiological factors in the PBPK model. In conclusion, our study is the first to suggest an optimal oral dosing regimen of bepotastine in pediatric patients using both approaches. This is expected to foster safer and more productive use of the drug.

Assessment of Pharmacokinetic Effects of Herbal Medicines on Escitalopram.

Purpose: Herbal medicines are occasionally used in combination with conventional antidepressants to mitigate various depression-associated symptoms. However, there is limited information on herb-antidepressant interactions. In this study, we investigated the pharmacokinetic (PK) effects of four herbal medicines (Gami-soyosan, Banhasasim-tang, Ojeok-san, and Bojungikgi-tang) on escitalopram, a commonly used antidepressant. Patients and Methods: In this open-label, fixed-sequence, three-period, crossover study, 18 participants were enrolled and divided into two groups. Each group received a 10 mg oral dose of escitalopram in period 1. Participants took escitalopram once daily and their assigned herbal medicines thrice a day for 7 d in periods 2 (group 1: Gami-soyosan, group 2: Ojeok-san) and 3 (group 1: Banhasasim-tang; group 2: Bojungikgi-tang). The primary endpoints were Cmax,ss and AUCtau,ss of escitalopram. Cmax,ss and AUCtau,ss in period 1 were obtained using nonparametric superposition from single-dose data. The PK endpoints were classified according to the CYP2C19 phenotype. Results: Of 18 participants, 16 completed the study. Systemic exposure to escitalopram resulted in a minor increase in the presence of each herbal medicine. The geometric mean ratios (GMRs, combination with herbal medicines/escitalopram monotherapy) and their 90% confidence intervals (CIs) for Cmax,ss and AUCtau,ss were as follows: Gamisoyosan- 1.1454 (0.9201, 1.4258) and 1.0749 (0.8084, 1.4291), Banhasasim-tang-1.0470 (0.7779, 1.4092) and 1.0465 (0.7035, 1.5568), Ojeok-san-1.1204 (0.8744, 1.4357) and 1.1267 (0.8466, 1.4996), and Bojungikgi-tang-1.1264 (0.8594, 1.4762) and 1.1400 (0.8515, 1.5261), respectively. Furthermore, no significant differences in the GMRs of Cmax,ss and AUCtau,ss were observed across different CYP2C19 phenotypes in any of the groups. Conclusion: The co-administration of escitalopram with Gami-soyosan, Banhasasim-tang, Ojeok-san, or Bojungikgi-tang did not exert significant PK effects on escitalopram. These findings provide valuable insights into the safe use of herbal medicines along with escitalopram.

Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics.

OBJECTIVE: Human multidrug and toxin extrusion member 2 (MATE2-K, SLC47A2) plays an important role in the renal elimination of various clinical drugs including the antidiabetic drug metformin. The goal of this study was to characterize genetic variants of MATE2-K and determine their association with the pharmacokinetics of metformin. METHODS: We screened DNA samples from 48 healthy Koreans for variants in the promoter and coding regions of MATE2-K and examined the function of common haplotypes in the promoter region using in-vitro luciferase assays. Then, the metformin pharmacokinetic study was carried out to determine the association between MATE2-K promoter haplotypes and metformin pharmacokinetics. RESULTS: Nine variants in the promoter region of MATE2-K and one nonsynonymous variant, p.G211V, were identified. The MATE2-K promoter haplotype 1 containing a known functional polymorphism, g.-130G>A and haplotype 2 containing two polymorphisms, g.-609G>A and g.-396G>A showed a significant increase in reporter activity. Among the 45 individuals who participated in the metformin pharmacokinetic study, 12 healthy Koreans who were homozygous for haplotype 1 or 2 showed a significant increase in renal clearance [539 ± 76 (reference group) vs. 633 ± 102 (variant group) ml/min; P=0.006] and secretion clearance [439 ± 81 (reference group) vs. 531 ± 102 (variant group) ml/min; P=0.007] of metformin compared with that shown by the reference group. CONCLUSION: Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin.

Influence of hepatic dysfunction on the pharmacokinetics and safety of fimasartan.

This study was designed to assess the pharmacokinetics (PK) and safety of fimasartan, an angiotensin II type 1 receptor blocker, in hepatic impairment patients as compared with healthy subjects. An open-label, single-dose, parallel study was conducted in 6 healthy male volunteers and 12 subjects with hepatic impairment. Healthy subjects were matched with hepatic dysfunction patients on the basis of age, gender, and body weight. After a single 120-mg oral administration of fimasartan, PK parameters and safety were analyzed between the hepatic dysfunction groups and healthy group. Compared with the healthy subjects, the geometric mean ratio and 90% confidence intervals for the maximum plasma concentration and the mean area under the plasma concentration-time curve from 0 to infinity (AUC)inf were 0.77 (0.24-2.47) and 1.11 (0.50-2.46), respectively, for the mild hepatic impairment and 6.55 (3.56-12.03) and 5.17 (4.19-6.37), respectively, for moderate hepatic impairment. However, there was no significant difference in time to peak plasma concentration (t(max)) and elimination half-life, and there were no serious or severe adverse events in all subjects. Subjects with mild hepatic impairment exhibited similar bioavailability compared with healthy subjects, whereas subjects with moderate hepatic impairment seemed to exhibit a higher level of systemic exposure to fimasartan than healthy subjects. In addition, all subjects were tolerable with fimasartan.

Pharmacokinetic and pharmacodynamic interaction of DWP16001, a sodium-glucose cotransporter-2 inhibitor, with phentermine in healthy subjects.

BACKGROUND: DWP16001, a sodium-glucose cotransporter-2 inhibitor, has shown promise for improving blood glucose control and facilitating weight loss. Co-administration with phentermine could enhance these effects. So, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of DWP16001 and phentermine. METHODS: We conducted a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study involving 24 healthy adults. Participants received either DWP16001 (2 mg), phentermine (37.5 mg), or a combination of both once daily for 7 days. Blood samples, urine samples, and body weights were collected to evaluate the PK and PD. RESULTS: The PK of the combination was found to be similar to that of the monotherapy. The geometric mean ratio (GMR) of Cmax,ss, and AUCtau,ss were 0.98 and 1.00, respectively, for DWP16001, and 1.01 and 0.94, respectively, for phentermine. Co-administration did not significantly affect the 24-hour urinary glucose excretion compared to DWP16001 monotherapy, and the GMR was 0.90. Participants tended to experience greater weight loss in the combination therapy group, and all demonstrated good tolerance. CONCLUSIONS: Our findings indicate that there were no significant interactions during co-administration. These results suggest that the combination of DWP16001 and phentermine may be safe and effective for the treatment of obesity and diabetes. CLINICAL TRIAL REGISTRATION: NCT05321732.

Pharmacokinetic and pharmacodynamic drug-drug interactions between evogliptin and empagliflozin or dapagliflozin in healthy male volunteers.

Evogliptin (EV) is a novel dipeptidyl peptidase-4 inhibitor (DPP4i) for glycemic control in patients with type 2 diabetes mellitus (T2DM). This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between EV and sodium glucose cotransporter-2 inhibitors (SGLT2i) in healthy volunteers since combination therapy of DPP4i and SGLT2i has been considered as an effective option for T2DM treatment. A randomized, open-label, multiple-dose, two-arm, three-period, three treatments, two-sequence crossover study was conducted in healthy Korean volunteers. In arm 1, subjects were administered 5 mg of EV once daily for 7 days, 25 mg of empagliflozin (EP) once daily for 5 days, and the combination once daily for 5 days (EV + EP). In arm 2, subjects were administered 5 mg of EV once daily for 7 days, 10 mg of dapagliflozin (DP) once daily for 5 days, and the combination once daily for 5 days (EV + DP). Serial blood samples were collected for PK analysis, and oral glucose tolerance tests were conducted for PD analysis. In each arm, a total of 18 subjects completed the study. All adverse events (AEs) were mild with no serious AEs. The geometric mean ratio and confidence interval of the main PK parameters (maximum concentration of the drug in plasma at steady state and area under the plasma drug concentration-time curve within a dosing interval at a steady state) between EV and either EP or DP alone were not significantly altered by co-administration. Administration of EV + EP or EV + DP did not result in significant PD changes, as determined by the glucose-lowering effect. Administration of EV + EP or EV + DP had no significant effects on the PK profiles of each drug. All treatments were well-tolerated.

Evaluation of pharmacokinetic interactions between lobeglitazone, empagliflozin, and metformin in healthy subjects.

Concomitant administration of lobeglitazone, empagliflozin, and metformin is expected to enhance blood glucose-lowering effects and improve medication compliance in patients with diabetes mellitus. In this study, we investigated the pharmacokinetic (PK) interactions and safety of lobeglitazone and co-administered empagliflozin and metformin, which are approved agents used in clinical settings. Two randomized, open-label, multiple-dose, 2-treatment, 2-period, 2-sequence crossover clinical trials (parts 1 and 2) were conducted independently. In part 1, lobeglitazone monotherapy or lobeglitazone, empagliflozin, and metformin triple therapy was administered for 5 days. In part 2, empagliflozin and metformin dual therapy or the abovementioned triple therapy were administered for 5 days. Serial blood samples were collected up to 24 hours after the last dose in each period for PK evaluation. The primary PK parameters (AUCtau,ss, Cmax,ss) of treatment regimens in each study part were calculated and compared. For lobeglitazone, the geometric mean ratios (GMRs) with 90% confidence intervals (CI) for triple therapy over monotherapy were 1.08 (1.03-1.14) for Cmax,ss and 0.98 (0.90-1.07) for AUCtau,ss. For empagliflozin, the GMRs and 90% CIs for triple therapy over dual therapy were 0.87 (0.78-0.97) for Cmax,ss and 0.97 (0.93-1.00) for AUCtau,ss. For metformin, the GMRs and 90% CIs for triple therapy over dual therapy were 1.06 (0.95-1.17) for Cmax,ss and 1.04 (0.97-1.12) for AUCtau,ss. All reported adverse events were mild. The triple therapy consisting of lobeglitazone, empagliflozin, and metformin did not show any clinically relevant drug interactions in relation to the PKs and safety of each drug substance. Trial Registration: ClinicalTrials.gov Identifier: NCT04334213.

Effect of Rifampicin on the Pharmacokinetics of Evogliptin in Healthy Volunteers.

Purpose: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics. Patients and Methods: An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference. Results: Maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC0-96h) of evogliptin with and without co-administration of rifampicin were compared. Reference and test Cmax and AUC0-96h values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration. Conclusion: Rifampicin decreased the AUC0-96h of evogliptin by 61.8% without significantly affecting Cmax. The mechanism underlying the decrease in AUC0-96h is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.

Effects of Hepatic Impairment on the Pharmacokinetic Profile and Safety of Lobeglitazone.

In this open-label, single-dose, parallel-group study, we compared the pharmacokinetic profile and safety of lobeglitazone, a thiazolidinedione acting as an agonist for peroxisome proliferator-activated receptors, in patients with hepatic impairment (HI) and healthy matched controls for age, sex, and body weight. After a single oral dose of lobeglitazone (0.5 mg), the lobeglitazone (parent drug) and M7 (major metabolite) plasma concentrations and pharmacokinetic parameters were analyzed and compared between the HI patient groups and healthy matched control groups. The geometric mean ratio (GMR; 90% confidence interval [CI]) for maximum concentration (Cmax ) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf ) of lobeglitazone was 1.06 (0.90-1.24) and 1.07 (0.82-1.40), respectively, for mild HI vs control A. The GMR (90%CI) of Cmax and AUCinf was 0.70 (0.56-0.88) and 1.00 (0.72-1.37), respectively, for moderate HI vs control B. For M7, the GMR (90%CI) of Cmax and AUCinf was 1.09 (0.75-1.57) and 1.18 (0.71-1.97), respectively, for mild HI vs control A and 1.50 (0.95-2.38) and 1.79 (1.06-3.04), respectively, for moderate HI vs control B. Notable adverse events or tolerability issues were not observed. Lobeglitazone may be safely used in patients with mild or moderate HI without dose adjustment.

Association between Daily Sunlight Exposure and Fractures in Older Korean Adults with Osteoporosis: A Nationwide Population-Based Cross-Sectional Study.

PURPOSE: We aimed to investigate the association between daily sunlight exposure duration and fractures in older Korean adults with osteoporosis. MATERIALS AND METHODS: We utilized data from the 2008-2011 Korea National Health and Nutrition Examination Survey. Osteoporosis was diagnosed based on a T-score of ≤-2.5 using dual energy X-ray absorptiometry. The duration of daily sunlight exposure and fracture were assessed via intensive health interviews by trained staff using standardized health questionnaires. Fracture was defined as one or more fractures of the femur, wrist, and spine. RESULTS: A total of 638 patients with osteoporosis aged ≥65 years were included. The odds ratio (OR) of total fractures was 0.55 times lower in the group with ≥5 h of daily sunlight exposure than in the group with <5 h of exposure after adjusting for age, sex, family history of osteoporosis or fracture, body mass index, bone mineral density of the femoral neck, serum 25-hydroxyvitamin D, current smoking, alcohol intake, daily calcium intake, and physical activity [95% confidence interval (CI) 0.31-0.97, p=0.040]. In patients with vitamin D insufficiency, the OR of total fracture was 0.52 times lower in the group with ≥5 h of daily sunlight exposure than in the group with less exposure after adjusting the above variables (95% CI 0.28-0.97, p=0.041). CONCLUSION: Sunlight exposure for ≥5 h a day was significantly associated with a decreased OR of fracture in older Korean adults with osteoporosis. This association was also significant in patients with vitamin D insufficiency.

Association Between 10-Year Fracture Probability and Nonalcoholic Fatty Liver Disease With or Without Sarcopenia in Korean Men: A Nationwide Population-Based Cross-Sectional Study.

Objective: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia, which are common in elderly men, are known as risk factors of fracture. However, few studies have examined the association with fracture in these patients. Therefore, we aimed to investigate the association between NAFLD with or without sarcopenia and 10-year fracture probability in Korean men aged ≥50 years. Materials and Methods: Data of 2,525 individuals from the 2010-2011 Korea National Health and Nutrition Examination Survey were analyzed. NAFLD was defined using the fatty liver index (FLI) and comprehensive NAFLD score (CNS), and liver fibrosis using the fibrosis 4 calculator. Sarcopenia was defined as the lowest quintile for sex-specific sarcopenia index cutoff; values. The Fracture Risk Assessment (FRAX) tool was used to predict the 10-year probability of major osteoporotic and hip fractures. Results: Compared to the no NAFLD group, the 10-year major osteoporotic fracture probability was significantly associated with the FLI-defined (ß = 0.16, P = 0.002) and CNS-defined (ß = 0.20, P < 0.001) NAFLD groups with liver fibrosis. Similarly, the 10-year hip fracture probability was significantly associated with the FLI- and CNS-defined NAFLD with liver fibrosis groups compared to the group without NAFLD (FLI-defined group, ß = 0.04, P = 0.046; CNS-defined group, ß = 0.05, P = 0.048). Furthermore, in the group with sarcopenia, the 10-year major osteoporotic fracture probability was significantly associated with the FLI- and CNS-defined NAFLD with liver fibrosis groups compared to the group without NAFLD (FLI-defined group, ß = 0.29, P = 0.003; CNS-defined group, ß = 0.38, P < 0.001). Conclusions: NAFLD with liver fibrosis is significantly associated with a higher 10-year major osteoporotic and hip fracture probability in Korean men aged ≥50 years, and this positive association was more profound in patients with sarcopenia. Therefore, screening middle-aged to elderly men who have NAFLD combined with liver fibrosis and sarcopenia may help prevent fractures.

Population Pharmacokinetics of Primaquine in the Korean Population.

While primaquine has long been used for malaria treatment, treatment failure is common. This study aims to develop a population pharmacokinetic model of primaquine and its metabolite, carboxyprimaquine, and examine factors influencing pharmacokinetic variability. The data was obtained from a clinical study in 24 Korean subjects randomly assigned to normal and obese groups. The participants received primaquine 15 mg daily for 4 days and blood samples were collected at day 4. Pharmacokinetic modeling was performed with NONMEM and using simulations; the influences of doses and covariates on drug exposure were examined. A minimal physiology-based pharmacokinetic model connected with a liver compartment comprehensively described the data, with CYP450 mediated clearance being positively correlated with the body weight and CYP2D6 activity score (p < 0.05). In the simulation, while the weight-normalized area under drug concentration for primaquine in the obese group decreased by 29% at the current recommended dose of 15 mg, it became similar to the normal weight group at a weight-normalized dose of 3.5 mg/kg. This study has demonstrated that the body weight and CYP2D6 activity score significantly influence the pharmacokinetics of primaquine. The developed model is expected to be used as a basis for optimal malaria treatment in Korean patients.

Comparison of the pharmacokinetics and pharmacodynamics of YH4808 in healthy subjects for defining an appropriate dosing regimen.

YH4808 is a novel potassium-competitive acid blocker developed for gastric acid-related disorders. Previous studies indicate its potential to improve symptoms of gastric acid-related disorders. The current study was aimed to find the optimal regimen of YH4808 for night time pH control. This study was performed in two parts. Each was a randomized, open-label, active-controlled, multiple-doses, two-treatment, two-period crossover study conducted in 20 healthy Korean volunteers. Subjects were randomly assigned to one of the four groups. The three groups received different dosage regimens of YH4808 (100 mg twice a day, 200 mg once a day, or 200 mg twice a day), and the fourth group received esomeprazole 40 mg twice a day. The pharmacokinetic parameters demonstrated that the systemic exposure of YH4808 increased in a dose-proportional manner. The difference in the proportion of time above pH 4 over 24 h from the baseline was the greatest in the group receiving YH4808 200 mg twice a day. The values of the area under the effect curve at night time (12 A.M.-7 A.M.) were higher in all YH4808 groups than in the esomeprazole group. However, the differences among the YH4808 groups were not statistically significant (p > 0.05). YH4808 exhibited potential for better pH control during the night in comparison to esomeprazole. The optimal regimen for night time pH control among all the YH4808 regimens was 200 mg twice a day. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01761513.

Association between daily sunlight exposure duration and diabetic retinopathy in Korean adults with diabetes: A nationwide population-based cross-sectional study.

PURPOSE: To investigate the association between daily sunlight exposure duration and diabetic retinopathy in Korean adults with diabetes. METHODS: This study used data from the 2008-2011 Korea National Health and Nutrition Examination Survey. Overall, 1,089 patients with diabetes aged >40 years were included. The duration of daily sunlight exposure was assessed via health interviews. Comprehensive ophthalmic evaluations, including standard retinal fundus photography after pupil dilation, were conducted. Diabetic retinopathy was graded using the modified Airlie House Classification. Multivariate logistic regression analysis was performed to analyze the association between daily sunlight exposure duration and the diagnosis of diabetic retinopathy and non-proliferative diabetic retinopathy. RESULTS: The risk of diabetic retinopathy was 2.66 times higher in the group with ≥5 h of daily sunlight exposure than in the group with less exposure after adjusting for risk factors such as duration of diabetes, serum hemoglobin A1c level, hypertension, and dyslipidemia (P = 0.023). Furthermore, the risk of non-proliferative diabetic retinopathy was 3.13 times higher in the group with ≥5 h of daily sunlight exposure than in the group with less exposure (P = 0.009). In patients with diabetes for <10 years, the risks of diabetic retinopathy and non-proliferative diabetic retinopathy were 4.26 and 4.82 times higher in the group with ≥5 h of daily sunlight exposure than the group with less exposure, respectively (P < 0.05). CONCLUSIONS: This study revealed that sunlight exposure for ≥5 h a day was significantly associated with an increased risk of diabetic retinopathy and non-proliferative diabetic retinopathy in Korean patients with diabetes. The risks were significantly higher in patients with diabetes for <10 years. Therefore, reducing daily sunlight exposure could be an early preventive strategy against diabetic retinopathy in people with diabetes.

A Population Pharmacokinetic and Pharmacodynamic Model of CKD-519.

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang's distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia.