Electronic medical records-based comparison of glycemic control efficacy between sulfonylureas and dipeptidyl peptidase-4 inhibitors added on to metformin monotherapy in patients with type 2 diabetes

Sulfonylurea (SU) and dipeptidyl peptidase-4 (DPP-4) inhibitors are most common secondary agents that are added to metformin monotherapy. Real-world studies have become increasingly important in providing evidence of treatment effectiveness in clinical practice and real-world data could help appropriate therapeutic information. Therefore, this study aims to compare the glycemic effectiveness of SU and DPP-4 inhibitors, which are added to metformin monotherapy in real clinical practice using electronic medical record (EMR) data. EMR data of type 2 diabetes patients treated at Seoul National University Hospital from December 2002 to December 2012 were retrieved and analyzed. The patients were divided into three groups: patients who maintained metformin monotherapy (M), and patients who added SU (MS) or DPP-4 inhibitors (MD) to metformin monotherapy. The mean change in HbA1c level, the proportion of patients achieving the HbA1c target < 7.0%, proportion of patients with treatment failure, and probability of treatment failure occurrence and changes in prescription were evaluated to compare glycemic control efficacy between SU and DPP-4 inhibitors. The MS showed significantly greater reduction in the Hb1Ac level than MD. The proportion of patients achieving HbA1c < 7.0% is higher in MD, whereas the proportion of patients with treatment failure was greater in MS. The probability of the treatment failure and probability of changes in the prescription were lower in MD than MS with hazard ratio of 0.499 and 0.579, respectively. In conclusion, this real-world study suggested that DPP-4 inhibitors are expected to show more durable glycemic control efficacy than SU in long-term use.

Electronic medical records-based comparison of glycemic control efficacy between sulfonylureas and dipeptidyl peptidase-4 inhibitors added on to metformin monotherapy in patients with type 2 diabetes

Sulfonylurea (SU) and dipeptidyl peptidase-4 (DPP-4) inhibitors are most common secondary agents that are added to metformin monotherapy. Real-world studies have become increasingly important in providing evidence of treatment effectiveness in clinical practice and real-world data could help appropriate therapeutic information. Therefore, this study aims to compare the glycemic effectiveness of SU and DPP-4 inhibitors, which are added to metformin monotherapy in real clinical practice using electronic medical record (EMR) data. EMR data of type 2 diabetes patients treated at Seoul National University Hospital from December 2002 to December 2012 were retrieved and analyzed. The patients were divided into three groups: patients who maintained metformin monotherapy (M), and patients who added SU (MS) or DPP-4 inhibitors (MD) to metformin monotherapy. The mean change in HbA1c level, the proportion of patients achieving the HbA1c target < 7.0%, proportion of patients with treatment failure, and probability of treatment failure occurrence and changes in prescription were evaluated to compare glycemic control efficacy between SU and DPP-4 inhibitors. The MS showed significantly greater reduction in the Hb1Ac level than MD. The proportion of patients achieving HbA1c < 7.0% is higher in MD, whereas the proportion of patients with treatment failure was greater in MS. The probability of the treatment failure and probability of changes in the prescription were lower in MD than MS with hazard ratio of 0.499 and 0.579, respectively. In conclusion, this real-world study suggested that DPP-4 inhibitors are expected to show more durable glycemic control efficacy than SU in long-term use.

Comparison of In Vivo Pharmacokinetics and Pharmacodynamics of Vancomycin Products Available in Korea

PURPOSE: Few studies have been investigated the in vivo efficacy of generic vancomycin products available outside of the United States. In this study, we aimed to compare the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of five generic vancomycin products available in Korea with those of the innovator.MATERIALS AND METHODS: The in vitro vancomycin purity of each product was examined using high-pressure liquid chromatography. Single-dose PK analyses were performed using neutropenic mice. The in vivo efficacy of vancomycin products was compared with that of the innovator in dose-effect experiments (25 to 400 mg/kg per day) using a thigh-infection model with neutropenic mice.RESULTS: Generic products had a lower proportion of vancomycin B (range: 90.3–93.8%) and a higher proportion of impurities (range: 6.2–9.7%) than the innovator (94.5% and 5.5%, respectively). In an in vivo single-dose PK study, the maximum concentration (C(max)) values of each generic were lower than that of the innovator, and the geographic mean area under the curve ratios of four generics were significantly lower than that of the innovator (all p<0.1). In the thigh-infection model, the maximum efficacies of generic products reflected in maximal effect (E(max)) values were not significantly different from the innovator. However, the PD profile curves of some generic products differed significantly from that of the innovator in mice injected with a high level of Mu3 (all p≤0.05).CONCLUSION: Some generic vancomycin products available in Korea showed inferior PK and PD profiles, especially in hetero-vancomycin-resistant mice infected with Staphylococcus aureus.

Development of a physiologically-based pharmacokinetic model for cyclosporine in Asian children with renal impairment

This study aimed to assess the pharmacokinetics of cyclosporine A (CsA) in Asian children with renal impairment (RI) by developing a physiologically-based pharmacokinetic (PBPK) model with Simcyp Simulator. The PBPK model of Asian children with RI was developed by modifying the physiological parameters of the built-in population libraries in Simcyp Simulator. The ratio of healthy and RI populations was obtained for each parameter showing a difference between the populations. Each ratio was multiplied by the corresponding parameter in healthy Asian children. The model verification was performed with published data of Korean children with kidney disease given multiple CsA administrations. Simulations were performed with different combinations of ethnicity, age, and renal function to identify the net impact of each factor. The simulated results suggested that the effect of RI was higher in children than adults for both Caucasian and Asian. In conclusion, the constructed model adequately characterized CsA pharmacokinetics in Korean children with RI. Simulations with populations categorized by ethnicity, age, and renal function enabled to assess the net impact of each factor on specific populations.

Pharmacokinetic characteristics of fluticasone, salmeterol and tiotropium after concurrent inhalation

Chronic obstructive pulmonary disease (COPD) is a type of progressive, obstructive lung disease characterized by long-term poor airflow. The symptoms of COPD may be relieved and its progression delayed by fluticasone (FTS), salmeterol (SM), and tiotropium (TTP). The aim of this study is to investigate pharmacokinetic (PK) characteristics of inhaled FTS, SM, and TTP after co-administration. An open-label, single-arm, three-period, simple ascending dose study was conducted in 10 healthy male subjects. A single dose of FTS/SM (250/50 µg) and TTP (18 µg) were concomitantly inhaled in period 1, and the dose of each drug was escalated to two- and three-fold in periods 2 and 3, respectively, with a 2-week washout between periods. Activated charcoal was co-administered before and after inhalation to block gastrointestinal absorption. Blood samples for PK analysis were collected up to 24 hours. PK parameters were obtained by non-compartmental analysis. FTS, SM, and TTP rapidly reached maximum plasma concentration after inhalation (0.08–3.00 h, 0.03–0.10 h and 0.03–0.10 h, respectively) and were eliminated with mean half-lives of 9.29–10.44 h, 6.09–12.39 h and 0.25–47.42 h, respectively. PK assessment of the lowest dose of TTP was limited due to relatively low systemic exposure compared to the lower limit of quantification. In conclusion, PK characteristics of FTS, SM, and TTP by pulmonary absorption were evaluated after concurrent inhalation. FTS and SM showed dose-proportional PK profiles between 250–750 µg and 50–150 µg, respectively, while TTP presented dose-proportionality in the early phase exposure between 18-54 µg.

Bioequivalence of the pharmacokinetics between two formulations of 0.2 mg tamsulosin hydrochloride in healthy subjects

Tamsulosin is an effective therapeutic option for lower urinary tract symptoms, as it selectively blocks alpha1A- and alpha1D-adrenoceptors in the bladder and prostate. The purpose of this study was to evaluate the bioequivalence in the pharmacokinetics (PK) of two 0.2 mg tamsulosin formulations when administered as the reference formulation (Yuropa(R) sustained-release tablet) vs. the test formulation (Yutanal(R) capsule) in healthy male subjects. A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 37 healthy volunteers. The 0.2 mg of tamsulosin as the test or the reference formulation were administered during each period, and serial blood samples were collected up to 36 hours after dosing for PK analyses. A non-compartmental analysis was used to estimate the PK parameters. Geometric mean ratios (GMR) and 90% confidence inter-vals (CIs) were calculated for the two formulations to compare the maximum concentration (Cmax) and the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast). The mean Cmax and AUClast for the test formulation were 6.19 microg/L and 71.30 microg.h/L, respectively, and 5.76 microg/L and 70.38 microg.h /L for the reference formulation, respectively. The GMRs (90% CIs) of the Cmax and AUClast between the two formulations were 1.09 (1.01-1.17) and 1.03 (0.96-1.10), respectively. Tamsulosin 0.2 mg as the test formulation exhibited bioequivalent PK profiles to those of the reference formulation. Therefore, the test formulation is expected to be an alternative to the reference formulation without concerns about differences in drug exposure.

Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

Donepezil is a centrally acting, reversible acetylcholinesterase inhibitor that is widely used for treating Alzheimer's disease. This study aimed to compare the pharmacokinetics of Bastia(R), a test tablet formulation of donepezil hydrochloride 10 mg, with those of Aricept(R), the reference tablet formulation of donepezil hydrochloride 10 mg, in healthy Korean male volunteers. A randomized, single-dose, two-way crossover study was conducted in 32 subjects. Subjects received a single dose of either test or reference compound and the alternate drug after a 4-week washout period. Serial blood samples for pharmacokinetic analysis were collected prior to dosing and periodically for 288 h after dosing for measurement of the plasma concentrations of donepezil. A non-compartmental method was used to estimate the pharmacokinetic parameters. The maximum concentration (C(max)) and the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC(288h)) for the two formulations were compared to evaluate bioequivalence. The C(max) of the test and reference drugs were 27.58+/-7.46 and 26.35+/-6.51 microg/L (mean+/-SD), respectively, while AUC(288h) was 1080.14+/-229.77 and 1043.07+/-242.28 microg.h/L (mean+/-SD), respectively. The geometric mean ratios (90% confidence interval) of the C(max) and AUC(288h) of the two tablets were 1.043 (0.990-1.099) and 1.039 (1.013-1.065). In conclusion, the newly formulated tablet of donepezil hydrochloride 10 mg is bioequivalent to the currently marketed 10 mg tablet.

Pharmacokinetic Characteristics of Cefcapene Pivoxil Hydrochloride after Single Oral Administration in Healthy Korean Subjects

BACKGROUND: Cefcapene pivoxil hydrochloride (CFPN-PI) is an oral ester cephalosporin antibiotic with a broad spectrum. In this study, we investigated the pharmacokinetics (PK) and tolerability of CFPN-PI following single oral administration in healthy Korean subjects. METHODS: An open label, dose escalation, parallel group study was conducted in 18 healthy male volunteers. A single dose of CFPN-PI was administered to 6 subjects in each treatment group of 100, 150 and 200 mg. Serial blood and urine samples were collected up to 12 h and 24 h after dosing, respectively. Plasma and urine concentrations of cefcapene were measured by HPLC-UV. PK parameters were estimated using non-compartmental analysis. For the safety evaluation, adverse event monitoring, clinical laboratory tests and physical examination were performed throughout the study. RESULTS: Median values of time to peak plasma concentration were observed around 1.5 to 2.0 h. Maximum plasma concentrations (Cmax) were 1.04 +/- 0.22, 1.24 +/- 0.46 and 1.56 +/- 0.43 mg/L (mean +/- SD), and area under the plasma concentration time curve (AUCinf) were 2.94 +/- 0.46, 3.97 +/- 1.28 and 4.70 +/- 1.19 h*mg/L in 100, 150 and 200 mg dose groups, respectively. The differences of dose normalized Cmax and AUCinf among three groups were not statistically significant. The fractions of drug excreted in urine unchanged were 31.5 % - 42.9 %. There were no serious adverse events or clinically significant abnormalities related to CFPN-PI. CONCLUSION: CFPN-PI was well tolerated with single oral administration and showed a linear PK property within 100 - 200 mg in healthy Korean male subjects.