Pharmacokinetic drug interaction between atorvastatin and ezetimibe in healthy Korean volunteers

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The aim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design crossover study was conducted in 36 healthy male subjects. During each period, the subjects received one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and free ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed the study. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasma concentration (Cmax,ss) and the area under the curve within a dosing interval at steady state (AUCτ,ss) of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799-1.2544) and 1.1154 (1.0079-1.2344), respectively. The corresponding values for total ezetimibe were 1.0005 (0.9227-1.0849) and 1.0176 (0.9465-1.0941). There was no clinically significant change in safety assessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibe showed similar PK and safety profile compared with each drug alone. The PK interaction between two drugs was not clinically significant in healthy Korean volunteers.ope

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.ope

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.ope

Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (Cmax) at 5-6 h post-dose, and had a long terminal half-life ranging between 40-70 h. The area under the plasma concentration-time curve (AUC) and Cmax increased with the dose, however, Cmax and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%-83%) was observed at 6-8 h post-dose. A sigmoid Emax model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC50 of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity.ope

Effects of JOINS® on the pharmacokinetic profiles of aceclofenac in healthy Korean volunteers: an open-label, multiple-dose, one sequence, two-period study

JOINS, an herbal anti-arthritic drug, was developed for the treatment and pain relief of knee osteoarthritis. It was approved for use in Korea by the Ministry of Food and Drug Safety in 2001. The aim of this study was to investigate the effect of JOINS on the pharmacokinetic (PK) profiles of aceclofenac in healthy adults. A PK drug-drug interaction study was conducted in 61 healthy subjects by using an open-label, multiple-dose, one sequence, two-period design. Blood samples were collected for plasma concentrations of aceclofenac during the reference period (aceclofenac 100 mg alone) and interaction period (aceclofenac 100 mg + JOINS 300 mg). The area under the curve within a dosing interval (τ) at steady state (AUCτ,ss) and the Cmax at steady state (Cmax,ss) of aceclofenac were analyzed by a non-compartment model using the Phoenix® WinNonlin® software version 6.3 (Pharsight, Mountain View, CA, USA). The 90% CIs of the geometric mean ratios (GMRs) of the AUCτ,ss of aceclofenac with JOINS to without JOINS (D4/D3 and D11/D3) were 0.9593?1.0130 and 0.9745?1.0291, respectively, and the corresponding values for the Cmax,ss of aceclofenac with JOINS to without JOINS (D4/D3 and D11/D3) were 0.8578?0.9795 and 0.8510?0.9717. Aceclofenac alone or co-administered with JOINS was safe and well tolerated with no serious adverse drug reactions or significant differences in the severity of adverse events (AEs) between the two treatment groups. We conclude that co-administration of aceclofenac with JOINS does not influence the PK and safety profiles of aceclofenac.ope

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 (β = 0.16, P = 0.002) and CNS-defined (β = 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, β = 0.04, P = 0.046; CNS-defined group, β = 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, β = 0.29, P = 0.003; CNS-defined group, β = 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.ope

A Case Report of Sepsis by Extended-Spectrum β-Lactamase Producing Escherichia Coli

The overall prognosis of acute pyelonephritis is good, but the infections by extended spectrum β-lactamase (ESBL) producing Escherichia coli (E.coli) cause poor responses to empirical antibiotic treatment, and consequently increase mortality. ESBL can hydrolyze the antibiotics with a β-lactam ring and confer resistance to oxyimino-cephalosporins and monobactams. If the patient shows poor responses to empirical antibiotics or severe septic conditions, physicians must switch the antibiotics to other antibiotics covering resistant strains without delay. We report a case of acute pyelonephritis by extended-spectrum β-lactamase producing E.coli in a 29-year-old woman who was empirically treated with oral ciprofloxacin as an initial treatment, but progressed to sepsisope

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.ope

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.ope

Pharmacodynamic evaluation of YH4808 for Helicobacter pylori eradication in healthy subjects

YH4808 is a novel selective potassium-competitive acid blocker demonstrated to be safe and to have inhibitory effects against gastric acid secretion in previous studies. A randomized, open-label, multiple-dose, 3-treatment, 1-period, parallel design study was conducted to compare the Helicobacter pylori eradication rates and acid suppression capacities of three regimens in 60 healthy subjects with H. pylori-positive, and the potential of YH4808 to replace proton-pump inhibitors (PPIs) in standard regimens for H. pylori eradication. Group 1 received YH4808, amoxicillin, and clarithromycin as a novel triple regimen, while Group 2 received YH4808 and amoxicillin only, and Group 3 received esomeprazole, amoxicillin, and clarithromycin, as the standard triple regimen. H. pylori eradication rates were 85.0% for Group 1, 25.0% for Group 2, and 83.3% for Group 3. Relative response rate between Group 1 and 3 was 1.02 (0.50-2.07; 95% CI, χ2 test p = 0.8881). Furthermore, the novel triple regimen, YH4808, amoxicillin, and clarithromycin, stably inhibited acid secretion and maintained a gastric pH greater than 4 or 5 for 24 hours, which was comparable to the pH range in the standard triple regimen. However, the onset times of the YH4808 regimens were earlier than that for the regimens using esomeprazole. There were no differences in the incidences or severity of adverse events among the three groups. Overall, the novel triple regimen was safe and well-tolerated. YH4808 could replace PPIs in standard triple regimens used for H. pylori eradication. Trial registration: ClinicalTrials.gov Identifier: NCT01921647.ope