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Translational and Clinical Pharmacology.2016;24(2):74-77. doi:10.12793/tcp.2016.24.2.74

This tutorial deals with basic concepts of volume of distribution, the second most important parameter in pharmacokinetics but often challenging for students in clinical pharmacology. Its relationships with dose, concentration and amount in the body are discussed using a physical model and examples of commonly used drugs, as well as its physiological aspects pertaining to the physical volume of differing organs. Finally, application of volume of distribution to the calculation of loading dose and half-life is used to show how it is essential in pharmacotherapy and clinical pharmacology.
Drug Therapy ; Half-Life ; Humans ; Pharmacokinetics ; Pharmacology, Clinical

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Statistical basis for pharmacometrics: random variables and their distribution functions, expected values, and correlation coefficient.

Kyungmee CHOI

Translational and Clinical Pharmacology.2016;24(2):66-73. doi:10.12793/tcp.2016.24.2.66

For pharmacometricians, probability theory is the very first obstacle towards the statistics since it is solely founded on mathematics. The purpose of this tutorial is to provide a simple version of introduction to a univariate random variable, its mean, variance, and the correlation coefficient of two random variables using as simple mathematics as possible. The definitions and theorems in this tutorial appear in most of the statistics books in common. Most examples are small and free of subjects like coins, dice, and binary signals so that the readers can intuitively understand them.
Mathematics ; Numismatics ; Probability Theory

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Problems within the post-marketing surveillance system in Korea: Time for a change.

Hyoyoung SONG ; Dong Seok YIM

Translational and Clinical Pharmacology.2016;24(2):63-65. doi:10.12793/tcp.2016.24.2.63

Post-marketing safety studies are an important tool for understanding and monitoring the safety profiles of drugs in the clinical setting. Their importance has attracted not only the attention of regulators for reinforcing legislation but also led to recent changes in European Union (EU) regulations; these regulations have influenced the practice of Post-Authorization Safety Study (PASS) by marketing authorization holders. Korea conducts post-marketing surveillance (PMS) studies, but their execution is very different. This editorial reviews the PMS system in Korea in comparison with the recent legislative changes affecting the EU system. Ultimately, it suggests that changes to the PMS system are necessary to obtain quality safety data while maintaining a global standard of operation. Such efforts to refine the system will enhance the credibility of the PMS in Korea and, in due course, produce safety profiles that will be valuable for public health.
European Union ; Korea* ; Marketing ; Public Health ; Social Control, Formal

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Erratum: Pharmacokinetics and bioequivalence of two different 20 mg olmesartan tablets: A randomized, single-dose, two-period crossover study in healthy Korean male volunteers.

Jieon LEE ; Anhye KIM ; Kyung Sang YU ; Jae Yong CHUNG ; Sung Vin YIM ; Bo Hyung KIM

Translational and Clinical Pharmacology.2016;24(2):111-111. doi:10.12793/tcp.2016.24.2.111

In the published version of this article, an error in the sponsor's identity was discovered in the acknowledgment section.

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Population pharmacokinetics and inter-laboratory variability of sildenafil and its metabolite after oral administration in Korean healthy male volunteers.

Sunil YOUN ; Wan Su PARK ; Gab Jin PARK ; Doo Yeon JANG ; Soo Hyeon BAE ; Seunghoon HAN ; Dong Seok YIM

Translational and Clinical Pharmacology.2016;24(2):105-110. doi:10.12793/tcp.2016.24.2.105

This study was to clarify population pharmacokinetics (PK) of sildenafil and its metabolite, N-desmethyl sildenafil (NDS) in Korean healthy male population using a pooled data from multiple clinical trials in consideration of inter-institution and inter-laboratory difference. A population PK analysis was performed with data of 243 healthy volunteers from five single-center (4 centers) comparative PK trials. The dataset included 7,376 sildenafil and NDS concentration (3,688 for each analyte) observed during 24 hours after the single dose of original sildenafil (either 50 mg or 100 mg of Viagra®). The plasma concentration was assayed in two laboratories. Various model structure was tested and the final model was evaluated using visual predictive checks. Demographic and clinical variables were assessed as potential covariates for PK parameters. A one-compartment first-order elimination model with proportional error was selected for the dispositional characteristics of sildenafil, and two-compartment model was chosen for NDS. Three transit compartments with Erlang-type absorption for fast absorption pathway and one compartment for slow absorption pathway constructed overall absorption model. The first-pass effect was rejected since it does not improve the model. The difference of NDS level by the bioanalysis laboratory was selected as the only covariate. Even though a direct comparison was difficult, the general trend in PK of sildenafil and NDS for Korean healthy male was considered similar to that of the other populations reported previously. It is recommended that the laboratory effect should be explored and evaluated when dataset is built using results from several laboratories.
Absorption ; Administration, Oral* ; Asian Continental Ancestry Group ; Dataset ; Healthy Volunteers ; Humans ; Male* ; Pharmacokinetics* ; Plasma ; Sildenafil Citrate* ; Volunteers*

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Population pharmacokinetics of imatinib mesylate in healthy Korean subjects.

Gab Jin PARK ; Wan Su PARK ; Soohyun BAE ; Sung Min PARK ; Seunghoon HAN ; Dong Seok YIM

Translational and Clinical Pharmacology.2016;24(2):96-104. doi:10.12793/tcp.2016.24.2.96

Imatinib (Gleevec™; Novartis Pharmaceuticals) is an orally administered protein-tyrosine kinase inhibitor. The goal of this study was to investigate the population pharmacokinetics (PK) of imatinib (as imatinib mesylate) in healthy male Koreans. A total of 1,773 plasma samples from 112 healthy male volunteers enrolled in three phase I clinical studies were used. Among the subjects, 76 received 400 mg and 36 received 100 mg as single oral doses. Peripheral blood sampling for PK analysis was done at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 60 and 72 (at 400 mg group) h after dosing. The firstorder conditional estimation with interaction method of NONMEM® (ver. 7.3) was used to build the population PK model. A two-compartment model with Weibull absorption and elimination gave the best fit to the data. The estimates of clearance (CL/F), volume of central compartment (Vc/F), intercompartmental clearance (Q/F), peripheral volume (Vp/F) and their interindividual variabily (%CV) were 13.6 L/h (23.4%), 153 L (29.2%), 8.64 L/h (35.9%) and 64 L (67%), respectively.
Absorption ; Humans ; Imatinib Mesylate* ; Male ; Methods ; Pharmacokinetics* ; Plasma ; Protein-Tyrosine Kinases ; Volunteers

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Effects of mirodenafil on the hemodynamics in hypertensive patients taking amlodipine.

Hyang Ki CHOI ; Eon Jeong SHIM ; Jihong SHON ; Jin Ah JUNG ; Jong Lyul GHIM ; Ji Hwa RYU ; Kyun Seop BAE ; Jae Gook SHIN

Translational and Clinical Pharmacology.2016;24(2):90-95. doi:10.12793/tcp.2016.24.2.90

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

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Pharmacokinetic comparison of two levofloxacin 100-mg tablet formulations and determination of time point appropriately reflecting its area under the curve.

Kyoung Ryun PARK ; Kyungho JANG ; Seunghwan LEE ; Kyung Sang YU ; Bo Hyung KIM ; Sung Vin YIM

Translational and Clinical Pharmacology.2016;24(2):84-89. doi:10.12793/tcp.2016.24.2.84

Levofloxacin is a broad-spectrum antibiotic with activity against gram-positive and -negative bacteria. This study compared the pharmacokinetics (PK) and evaluated the bioequivalence of two levofloxacin 100-mg tablet formulations. An open, randomized, two-way crossover study was conducted in 28 healthy volunteers. The reference (Cravit Tab 100-mg, Jeil) or test (Levobacter Tab, Seoul) formulation was administered and serial blood samples were collected over 24 h for PK analysis. Levofloxacin plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The correlation of levofloxacin concentration at various time points with the area under the concentration time-curve over the time interval from 0 extrapolated to infinity (AUCinf) was estimated to determine the best reflected time point. The average half-life, maximum plasma concentration (Cmax), and AUClast were comparable. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR test/reference) of AUClast and Cmax were 0.8200-1.0633 and 0.9474-1.0643 respectively. Both formulations were tolerated with no clinically relevant safety issues. Plasma levofloxacin concentrations at various time points correlated well with the AUCinf, and showed high correlation coefficients (r > 0.7, P < 0.001) for both drugs 8 and 12 h after administration. Both formulations showed similar PK profiles while levofloxacin plasma levels after administration indicated their bioequivalence. The Cmax and AUClast GMR 90% CIs were 0.80-1.25. Moreover, 12 h was the best time point to predict the AUCinf and therefore suitable for therapeutic drug monitoring.
Bacteria ; Cross-Over Studies ; Drug Monitoring ; Half-Life ; Healthy Volunteers ; Levofloxacin* ; Mass Spectrometry ; Pharmacokinetics ; Plasma ; Therapeutic Equivalency

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Evaluation of factors associated with drug-induced liver injury using electronic medical records.

Hyewon CHUNG ; Hyungmi AN ; Jieon LEE ; Jaeseong OH ; Kyung Sang YU ; Jae Yong CHUNG

Translational and Clinical Pharmacology.2016;24(2):78-83. doi:10.12793/tcp.2016.24.2.78

The causes and attributing factors of drug-induced liver injury (DILI) remain unclear as a result of exclusion-based diagnosis and low incidence. The aim of this study was to explore and evaluate potential drug-related causes and factors associated with DILI. Using electronic medical records (EMR) from the Seoul National University Bundang Hospital from 2003 to 2014, patients with DILI events were identified based on liver function test results. All patients with hepatic or biliary diseases were excluded. Patient characteristics, including demographics, clinical patterns, and severity of DILI were summarized and their associations were evaluated. Drugs frequently prescribed to patients exhibiting DILI within the month before their first DILI event compared to the total patient population were identified and the probabilities of hepatotoxicity associated with their use were assessed through examination of available reports. Among the 1,835 patients with laboratory test results, 1,023 were male and 1,053 were 65 years of age or older. Moderate DILI was dominant in older or male patients and cholestatic DILI tended to be more frequently identified in older patients of either sex. Cytarabine was the most frequently prescribed drug in DILI patients, followed by aprotinin and dopamine. Among the 30 most frequently prescribed drugs in DILI patients, 15 (50%) were identified as known hepatotoxic agents. In conclusion, this study evaluated differences in features of DILI among groups based on demographics and explored candidate drugs with possible associations with DILI, which has potential value reflecting real-world clinical practice.
Aprotinin ; Cytarabine ; Demography ; Diagnosis ; Dopamine ; Drug-Induced Liver Injury* ; Electronic Health Records* ; Humans ; Incidence ; Liver Function Tests ; Male ; Seoul

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Development of a LC-MS/MS for Quantification of Venlafaxine in Human Plasma and Application to Bioequivalence Study in healthy Korean Subjects.

Hyun Ku KANG ; Min A KANG ; Hyun Jin KIM ; Yoo Sin PARK ; Shin Hee KIM ; Ju Seop KANG

Translational and Clinical Pharmacology.2014;22(1):35-42. doi:10.12793/tcp.2014.22.1.35

A simple, rapid and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is developed and validated for quantification of venlafaxine in human plasma with simple liquid-liquid extraction step consisted of extraction with ether and dichloromethane for 10 min and mixing with 1 M sodium acetate in human plasma using fluoxetine as an internal standard (IS). The analyte are separated using an isocratic mobile phase consisted of acetonitrile and 5 mM ammonium formate (4/3, v/v) on a isocratic YMC hydrosphere C18 (2.0x50.0 mm, 3.0 microm) column and analyzed by MS/MS in the multiple reaction monitoring (MRM) mode using the transitions of respective [M+H](+) ions, m/z 278.2-->260.3 and m/z 310.1-->148.1 for quantification of venlafaxine and IS, respectively. The standard calibration curves showed good linearity within the range of 1.0-200.0 ng/mL (r2=0.9986, 1/chi2 weighting). The lower limit of quantification (LLOQ) was 1.0 ng/mL. The retention times of venlafaxine and IS were 0.6 min and 0.7 min that means the potential for the high-throughput potential of the proposed method. In addition, no significant metabolic compounds were found to interfere with the analysis. Acceptable precision and accuracy were obtained for the concentrations over the standard curve range. The validated method was successfully applied to bioequivalence study after 75-mg of venlafaxine sustained-release (SR) capsule in 24 healthy Korean subjects.
Ammonium Compounds ; Calibration ; Chromatography, Liquid ; Ether ; Fluoxetine ; Humans ; Ions ; Liquid-Liquid Extraction ; Methylene Chloride ; Pharmacokinetics ; Plasma* ; Sodium Acetate ; Tandem Mass Spectrometry ; Therapeutic Equivalency* ; Venlafaxine Hydrochloride

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