• 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.

• Journal of Pharmaceutical Investigation
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• v.39 no.2
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• pp.111-115
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• 2009

The pharmacokinetics of cyclosporin A (CsA) after single and multiple oral dosing of new CsA self-micro-emulsifying drug delivery system (SMEDDS) in dogs were estimated. A single dose study was performed following a two-way crossover design against six dogs with reference SMEDDS. For a multiple dose study, three dogs were allocated for each drug, and 100 mg of drug was administered daily for 6 days. Whole blood concentration of CsA was analyzed by radio-immunoassay. Both drug showed identical blood concentration profiles in both studies, and no statistical difference was detected in pharmacokinetic parameters. The relative bioavailabilities of test SMEDDS were 91.4% and 89.1%, respectively, in the single dose study and the last day of multiple dose study. Especially, multiple dose study proved the good relationship between C-0/C-2 and AUC for reference SMEDDS, which is an indispensable part of therapeutic drug monitoring. These results suggest newly formulated CsA SMEDDS possibly shows identical pharmacokinetics and pharmacodynamic behaviors in clinical trials.

• The Journal of Korean Medicine
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• v.31 no.3
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• pp.1-7
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• 2010

Objectives: To introduce to TKM scientific dose conversion methods of human to animal or animal to human for new drug investigations. Methods: We searched guidelines of the FDA and KFDA, and compared them with references for drug-dose conversion from various databases such as PubMed and Google. Then, we analyzed the potential issues and problems related to dose conversion in safety documentation of new herbal drugs based on our experiences during Investigational New Drug (IND) applications of TKM. Results: Dose conversion from human to animal or animal to human must be appropriately translated during new drug development. From time to time, investigators have some difficulty in determining the appropriate dose, because of misunderstandings of dose conversion, especially when they estimate starting dose in clinical or animal studies to investigate efficacy, toxicology and mechanisms. Therefore, education of appropriate dose calculation is crucial for investigators. The animal dose should not be extrapolated to humans by a simple conversion method based only on body weight, because many studies suggest the normalization method is based mainly on body surface area (BSA). In general, the body surface area seems to have good correlation among species with several parameters including oxygen utilization, caloric expenditure, basal metabolism, blood volume and circulating plasma protein. Likewise, a safety factor should be taken into consideration when deciding high dose in animal toxicology study. Conclusion: Herein, we explain the significance of dose conversion based on body surface area and starting dose estimation for clinical trials with safety factor.

• The Transactions of The Korean Institute of Electrical Engineers
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• v.56 no.1
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• pp.174-182
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• 2007

In this paper, we study the influence of infection ratio on gradual reduction of drug dose for the five state HIV infection model that explicitly includes the population of the virus. We first compute all equilibrium points of the model and investigate the stabilities of them. As a result, a bifurcation diagram is obtained which shows a change in the equilibrium points, or in their stability properties, as the drug effect $\eta$ is varied from 0 to 1(alternatively, drug dose is changed from 1 to 0). Based on the bifurcation diagram, we show that the gradual reduction of drug dose can be applied for the treatment of AIDS patients. Moreover, we analyze the influence of the variation of infection ratio on the gradual reduction treatment. Computer simulation results are also presented to validate the proposed results.

• Journal of Pharmaceutical Investigation
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• v.31 no.1
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• pp.19-25
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• 2001

The purpose of this study was to use a ternary polymeric matrix system for high drug loading of a highly soluble drug for controlled release delivery. The controlled drug delivery of diltiazem HCl (solubility > 50% in water at $25^{\circ}C$) with high loading dose (the final loading dose of drug was 34%) from a ternary polymeric matrix (gelatin, pectin, HPMC) was successfully accomplished. This simple monolithic system with 240 mg drug loading provided near zero-order release over a 24 hour-period by which time the system was completely dissolved. The release kinetics of diltiazem HCl tablet with high loading dose from the designed ternary polymeric system was dependent on the ratios of HPMC : pectin binary mixture. The release rate increased as pectin : HPMC ratio were increased. Swelling behavior of the ternary system and the ionic interaction of formulation components with cationic diltiazem molecule appear to control drug diffusion and the release kinetics. Comparable release profiles between commercial product and the designed system were obtained. The binding study between gelatin with diltiazem HCl showed the presence of two binding sites for drug interaction with subsequent controlled diffusion upon swelling. This designed delivery system is easy to manufacture and drug release behavior is highly reproducible and offers advantages over the existing commercial product.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.414.2-414.2
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• 2002

To secure the safety of drugs without compromising drug efficacy, it can not be more important to administer the exact intended amount of active ingredients to patients. Even if the correct amount of drugs are taken in the correct manner, drug can be overdosed or less-dosed without intention unless the content uniformity of the unit dose were secured. Especially, it can be a serious problem when it comes to drugs with narrow therapeutic windows or a strong pharmacological activity at a small dose. (omitted)

• Archives of Pharmacal Research
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• v.18 no.6
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• pp.427-433
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• 1995

A microscopic mass balance approach has hsown that the initial saturation (Is), absorption number (An), dose number (Do), and dissolution number (Dn) are four fundamental dimensionless parameters that can be used to estimate the fraction dose absorbed (F)l of suspensions of poorly soluble drugs in humans. The dissolution number of a drug increases with decreasing its particle size. The effect of micronization on F for suspensions was investigated in terms of Dn. About 90% of maximal F can be achieved at $Dn{\approx}2$. Increasing the solubility of a drug results in better oral absorption through increasing Dn and decreasing the solubility of a drug results in better oral absorption through increasing Dn and decreasing Do. The fractions dose absorbed of digoxin, griseofulvin, and benoxaprofen agree with predicted F values sorbed by reducing particle size, while absorption of drugs with high Do and low Dn is limited by solubility and requires higher solubility to enhance the fraction dose absorbed in addition to micronization. Solubility at the physiological pH should be used for the estimation of the fraction dose absorbed.

• Archives of Pharmacal Research
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• v.17 no.5
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• pp.364-370
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• 1994

A microscopic mass balance approach has been developed to estimate the extent and rate of absorption for camier-mediated comounds. For the case competitive inhibition in the presence of an inhibitor which shares the same camier, the fraction dose absorbed (F) and absorption rate constant ($K_a$) of a drug can be calculated from its concentration profile in the intestinal lumen. Absorption parameters obtained by single-pass perfusion experiments were used in the simultaion of the absorption of some aminopenicilins. Predicted fractions dose absorbed and absorption rate constants of ampicilin and amoxicilin were significantly reduced in the presence of a 6-times higher molar dose of cyclacilin. The drug-drug interactions on the competitive absroption of camier-mediated compounds were determined with regard to F and $K_a$. Predicted decreases in F for some aminopenicilins corrlated well with decrease in the urinary recovery in humans reported in the literature. Predicted decrease in the mean absorption rate constant ($\barK_a$) explain the delays in the time of peak plasma concentration ($T_{max}$) reported in humans.

• Journal of Convergence for Information Technology
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• v.7 no.4
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• pp.45-51
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• 2017

The purpose of this study is to find the level of drug dose calculations and confidence of nursing students who completed fundamental nursing. After receiving informed consent, questionnaires and drug dose calculation paper of 152 subjects were collected. The data were analyzed using SPSS 19.0. The $mean{\pm}SD$ of drug dose calculations was $7.46{\pm}1.97$ on a scale of 10, the mean score of male students was higher than female's(t=3.64, p=.001), and the mean score of science was higher than vocational's according to high school departments(F=5.11, p=.007). In the score of confidence, the $mean{\pm}SD$ was $4.12{\pm}1.12$ on a scale of 6, the mean score of male students was higher than female's(t=8.94, p=.001), and the science was higher than humanity or vocational(F=6.28, p=.002). There was a positive correlation between drug dose calculation and confidence scores(r= .32, p=.001), and explanation rate of confidence on drug dose calculation was 10.2%(p=0.001) in regression analysis. This suggests that nursing students need to improve drug dose calculation ability by strengthening confidence.

• Journal of Pharmaceutical Investigation
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• v.34 no.4
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• pp.299-303
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• 2004

Prescription filling in powder form is performed in community pharmacy practice to adjust dose for children and patients who cannot swallow whole tablet. However, there are few reports regarding the stability of the active ingredient and possible microbial growth after the medication is dispensed to powder form. This study examined the stability of atenolol, an antihypertensive agent, and microbial growth in the unit dose pouches dispensed at twenty-one community pharmacies located in Taegu area. Randomly chosen first unit dose pouch contained 77.4% of the prescribed dose of the drug and there were only four community pharmacies that dispensed the drug within 10% deviation from the dose prescribed by physician. Surprisingly, there were three community pharmacies that dispensed the drug with greater than 40% deviation, which may pose a major concern regarding the efficacy and safety of the drug prescribed for the treatment of hypertension. Atenolol content during a month did not indicate significant change, showing 5.4%, 4.3%, and 3.3% of decrease in 50%, 80%, and 90% relative humidity conditions, respectively. Microbiological examination during a month showed less than 0.5 microorganism in high power field (hpf) in all the relative humidity conditions tested. Based on this study, pharmacy practice in community pharmacy needs to be rigorously regulated to ensure that the dose of the prescribed drug is properly incorporated into the unit dose pouch dispensed as powder form.