• Korean Journal of Clinical Pharmacy
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• v.21 no.4
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• pp.339-346
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• 2011

Over the past few decades, drug regulatory agencies in advanced countries have been emphasizing pharmacometrics as a tool for an effective and efficient drug evaluation. Despite this international movement, the value of pharmacometrics is still poorly recognized by the Korean drug evaluation system. This study aimed to analyze the current state of utilization of pharmacometrics by foreign drug regulatory agencies and develop a road map to guide the implementation pharmacometrics into the Korean drug evaluation system. MEDLINE and foreign drug regulatory agency database were extensively searched to obtain scientific research articles, guidance, regulations and pharmacometric review reports on foreign pharmacometric drug evaluation system. A systematic roadmap comprised of 3 stages to implement pharmacometrics in Korean drug evaluation system was formulated after analyzing the collected data in tune with the current evaluation system. Pharmacometrics is an urgently required tool to achieve an efficient drug evaluation and review in Korea. The road map developed by this study is expected to aid in setting up a policy to implement and utilize pharmacometrics in Korea.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.6
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• pp.545-553
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• 2021

Fixed-dose combinations development requires pharmacokinetic drugdrug interaction (DDI) studies between active ingredients. For some drugs, pharmacokinetic properties such as long half-life or delayed distribution, make it difficult to conduct such clinical trials and to estimate the exact magnitude of DDI. In this study, the conventional (non-compartmental analysis and bioequivalence [BE]) and model-based analyses were compared for their performance to evaluate DDI using amlodipine as an example. Raw data without DDI or simulated data using pharmacokinetic models were compared to the data obtained after concomitant administration. Regardless of the methodology, all the results fell within the classical BE limit. It was shown that the model-based approach may be valid as the conventional approach and reduce the possibility of DDI overestimation. Several advantages (i.e., quantitative changes in parameters and precision of confidence interval) of the model-based approach were demonstrated, and possible application methods were proposed. Therefore, it is expected that the model-based analysis is appropriately utilized according to the situation and purpose.

• Translational and Clinical Pharmacology
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• v.26 no.4
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• pp.166-171
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• 2018

Although there are many commercially available training software programs for pharmacokinetics, they lack flexibility and convenience. In this study, we develop simulation software to facilitate pharmacokinetics education. General formulas for time courses of drug concentrations after single and multiple dosing were used to build source code that allows users to simulate situations tailored to their learning objectives. A mathematical relationship for a 1-compartment model was implemented in the form of differential equations. The concept of population pharmacokinetics was also taken into consideration for further applications. The source code was written using R. For the convenience of users, two types of software were developed: a web-based simulator and a standalone-type application. The application was built in the JAVA language. We used the JAVA/R Interface library and the 'eval()' method from JAVA for the R/JAVA interface. The final product has an input window that includes fields for parameter values, dosing regimen, and population pharmacokinetics options. When a simulation is performed, the resulting drug concentration time course is shown in the output window. The simulation results are obtained within 1 minute even if the population pharmacokinetics option is selected and many parameters are considered, and the user can therefore quickly learn a variety of situations. Such software is an excellent candidate for development as an open tool intended for wide use in Korea. Pharmacokinetics experts will be able to use this tool to teach various audiences, including undergraduates.

• Korean Journal of Clinical Pharmacy
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• v.26 no.2
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• pp.150-162
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• 2016

Objective: First-in-human dose estimation is an essential approach for successful clinical trials for drug development. In this study, we systematically compared first-in-human dose and human pharmacokinetic parameter estimation approaches. Methods: First-in-human dose estimation approaches divided into similar drug comparison approaches, regulatory guidance based approaches, and pharmacokinetic based approaches. Human clearance, volume of distribution and bioavailability were classified for human pharmacokinetic parameter estimation approaches. Results: Similar drug comparison approaches is simple and appropriate me-too drug. Regulatory guidance based approaches is recommended from US Food and Drug Administration (FDA) and European Medicines Agency (EMA) regarding no-observed-adverse-effect level (NOAEL) or minimum anticipated biological effect level (MABEL). Pharmacokinetic based approaches are 8 approaches for human clearance estimation, 5 approaches for human volume of distribution, and 4 approaches for human bioavailability. Conclusion: This study introduced and compared all methods for first-in-human dose estimation. It would be useful practically to estimate first-in-human dose for drug development.

• The Korean Journal of Applied Statistics
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• v.28 no.2
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• pp.175-188
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• 2015

This study is about estimation methods for the population pharmacokinetic and pharmacodymic model. This is a nonlinear mixed effect model, and it is difficult to find estimates of parameters because of nonlinearity. In this study, we examined theoretical background of various estimation methods provided by NONMEM, which is the most widely used software in the pharmacometrics area. We focused on estimation methods using a stochastic sampling approach - IMP, IMPMAP, SAEM and BAYES. The SAEM method showed the best performance among methods, and IMPMAP and BAYES methods showed slightly less performance than SAEM. The major obstacle to a stochastic sampling approach is the running time to find solution. We propose new approach to find more precise initial values using an ITS method to shorten the running time.

• Mass Spectrometry Letters
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• v.8 no.2
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• pp.23-28
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• 2017

Arctigenin is the main active ingredient of Fructus Arctii, which has been reported with a variety of therapeutic activities including anti-cancer, anti-inflammation, anti-virus, and anti-obesity effects. In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of arctigenin in rat plasma. The assay utilized a simple protein precipitation with methanol and the mobile phase consisted of 100% methanol and water containing 0.1% formic acid (65:35 v/v). Arctigenin and the internal standard (psoralen) were monitored using a positive electrospray turbo ionspray mode with multiple reaction monitoring transitions of m/z $373.2{\rightarrow}136.9$ and m/z $187.2{\rightarrow}130.9$, respectively, and total chromatographic run time was within 5 min. The lower limit of quantification (LLOQ) of arctigenin was 5 ng/mL in the rat plasma. The intra- and inter-day accuracy of arctigenin at LLOQ and matrix-matched quality control samples ranged 97.4 - 104.8% and 97.2 - 102.0%, respectively. The intra-day precision was within 4.80% and the inter-day precision was within 5.92%. Application of the present method was demonstrated through a pharmacokinetic study after intravenous and oral administration of arctigenin in male Sprague Dawley rats.