One of the important purposes in population pharmacokinetic studies is to investigate the relationships between parameters and covariates to describe parameter variability. The purpose of this study is to evaluate the model's ability to correctly detect the parameter-covariate relationship that can be observed in phase I clinical trials. Data were simulated from a two-compartment model with zero-order absorption and first-order elimination, which was built from valsartan's concentration data collected from a previously conducted study. With creatinine clearance (CLCR) being used as a covariate to be tested, 3 different significance levels of 0.001clinical trial, we hope that this work can provide an insight into covariate selectivity associated with healthy volunteer data.
Absorption ; Clinical Trials, Phase I as Topic* ; Creatinine ; Dataset ; Healthy Volunteers ; Hope

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.
Acetylcholinesterase ; Alzheimer Disease ; Cross-Over Studies ; Humans ; Male ; Pharmacokinetics ; Plasma ; Tablets ; Therapeutic Equivalency* ; Volunteers*

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.
Cross-Over Studies ; Healthy Volunteers ; Humans ; Lower Urinary Tract Symptoms ; Male ; Pharmacokinetics* ; Prostate ; Therapeutic Equivalency* ; Urinary Bladder

Primary health care providers play a critical role in maintaining public health, and the appropriate prescription of pharmaceutical products is a major component of their practice. This series of articles entitled 'Clinical Pharmacology Review for Primary Health Care Providers' is intended to help primary health care providers select more appropriate prescriptions for frequently used drugs based on up-to-date information. We expect that this effort will contribute to improvements in public health and diminish unnecessary drug use.
Drug Interactions ; Pharmaceutical Preparations ; Pharmacology ; Pharmacology, Clinical* ; Prescriptions ; Primary Health Care* ; Public Health ; Steroids*

The maximum likelihood estimator is the point estimator of the top priority in statistical data analysis because of its optimum properties for large sample size. While the maximum likelihood estimator is widely used, it has been an abstruse subject for pharmacometricians without statitics bagkround because of high dimensional calculus and asymptotic theories. This tutorial provides a general and brief introduction to the maximum likelihood estimator and its related caluculus for non-statisticians.
Calculi ; Data Interpretation, Statistical ; Sample Size

NONMEM(R) is the most-widely used nonlinear mixed effects modelling tool introduced into population PK/PD analysis. Even though thousands of pharmaceutical scientists utilize NONMEM(R) routinely for their data analysis, the various estimation methods implemented in NONMEM(R) remain a mystery for most users due to the complex statistical and mathematical derivations underlying the algorithm used in NONMEM(R). In this tutorial, we demonstrated how to directly obtain the objective function value and post hoc eta for the first order approximation method by the use of R. We hope that this tutorial helps pharmacometricians understand the underlying estimation process of nonlinear mixed effects modelling.
Hope ; Reproduction* ; Statistics as Topic

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 (C(max,ss)) and the area under the curve within a dosing interval at steady state (AUC(τ,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.
Atorvastatin Calcium* ; Cholesterol ; Cross-Over Studies ; Drug Interactions* ; Dyslipidemias ; Ezetimibe* ; Humans ; Lipoproteins ; Male ; Pharmacokinetics ; Plasma ; Volunteers*

JOINS (SKI306X) is an herbal anti-arthritic medicine that is widely used with aceclofenac for treating osteoarthritis in Korea. A fixed-dose combination (FDC) tablet containing SKI306X and aceclofenac was developed to improve patient compliance. This study aimed to compare the pharmacokinetics (PK) and safety of the FDC tablet with those of co-administered SKI306X and aceclofenac in healthy subjects. In this randomized, open-label, two-way crossover, single-dose study, the FDC tablet (SKI306X 300 mg/aceclofenac 100 mg) (test) was given or co-administration of 300 mg of SKI306X and 100 mg of aceclofenac (reference) was performed followed by a 7-day wash-out period. Blood samples were collected before and after drug administration to evaluate aceclofenac PK parameters, and safety was assessed throughout the study. A total of 54 healthy male subjects were enrolled in and completed the study. T(max) and t(1/2) of aceclofenac of the FDC tablet were similar to those of aceclofenac co-administered with SKI306X (T(max): test 2.96 h and reference 2.14 h; t(1/2): test 3.46 h and reference 4.04 h). The geometric mean ratios (90% confidence intervals) of C(max) and AUC(last) (T/R) were 0.85 (0.81 to 0.91) and 1.03 (1.01 to 1.06) respectively; these results were within the predefined range (0.8 to 1.25). There was only one drug-related adverse event (dizziness) occurred after administration of the FDC tablet; however, it was mild in severity and resolved without any complications. The FDC tablet was well tolerated and exhibited an absorption rate and extent comparable to those of SKI306X and aceclofenac administered simultaneously.
Absorption ; Healthy Volunteers* ; Humans ; Korea ; Male ; Osteoarthritis ; Patient Compliance ; Pharmacokinetics* ; Tablets*

Two separate studies were conducted to establish bioequivalence (BE) for two doses of atorvastatin/metformin sustained-release (SR) fixed dose combination (FDC) versus the same dosage of the individual component (IC) tablets in healthy male subjects under fed conditions (study 1, BE of atorvastatin/metformin SR 20/500 mg FDC; study 2, BE of atorvastatin/metformin SR 20/750 mg FDC). Each study was a randomized, open-label, single oral dose, two-way crossover design. Serial blood samples were collected pre-dose and up to 36 hours post-dose for atorvastatin and 24 hours for metformin. Plasma concentrations of atorvastatin, 2-OH atorvastatin and metformin were analyzed using a validated liquid chromatography tandem mass-spectrometry. A non-compartmental analysis was used to calculate pharmacokinetic (PK) variables and analysis of variance was performed on the lognormal-transformed PK variables. A total of 75 subjects completed the study 1 (36 subjects) and study 2 (39 subjects). The 90% confidence intervals for the adjusted geometric mean ratio of Cmax and the AUC0-t were within the predefined 0.80 to 1.25 range. The number of subjects reporting at least one adverse event following FDC treatments was comparable to that following IC treatments. The two treatments were well tolerated. Therefore, atorvastatin/metformin SR 20/500 mg and 20/750 mg FDC tablets are expected to be used as alternatives to IC tablets to decrease the pill burden and increase patient compliance.
Atorvastatin Calcium* ; Chromatography, Liquid ; Cross-Over Studies* ; Humans ; Male* ; Metformin* ; Patient Compliance ; Pharmacokinetics* ; Plasma ; Tablets* ; Therapeutic Equivalency

This study describes the development of an analytical method to determine radotinib levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) for pharmacokinetic application. Plasma samples were sequentially processed by liquid-liquid extraction using methyl tert-butyl ether, evaporation, and reconstitution. Analytes were separated and analyzed using HPLC-MS/MS in selected reaction monitoring mode, monitoring the specific transitions of m/z 531 to 290 for radotinib and m/z 409 to 238 for amlodipine (internal standard). The HPLC-MS/MS analytical method was validated with respect to selectivity, linearity, sensitivity, accuracy, precision, recovery, and stability. Calibration curves were linear over a concentration range 5–3,000 ng/mL with correlation coefficients (r) > 0.998. The lower limit of quantification for radotinib in plasma was 5 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. This method was suitable to determine radotinib levels in human plasma because of its simplicity, selectivity, precision, and accuracy.
Amlodipine ; Calibration ; Chromatography, Liquid ; Ether ; Humans* ; Liquid-Liquid Extraction ; Mass Spectrometry* ; Methods* ; Plasma* ; Quality Control ; Tandem Mass Spectrometry