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      Drug Design, Development and Therapy (submit here)

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      New tablet formulation of tacrolimus with smaller interindividual variability may become a better treatment option than the conventional capsule formulation in organ transplant patients


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          To evaluate the pharmacokinetic (PK) and tolerability profiles of a new tablet formulation of tacrolimus and its interindividual variability (IIV) in the systemic exposure, and to compare them with those of the conventional capsule formulation, a randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in 47 healthy males. The capsule or tablet formulation of tacrolimus was orally administered, and serial blood samples were collected up to 96 hours after dosing. Whole-blood tacrolimus concentration was determined using liquid chromatography–tandem mass spectrometry. The maximum whole-blood tacrolimus concentration (C max) and the area under the whole-blood tacrolimus concentration–time curve from 0 hour to the last quantifiable concentration (AUC last) were compared between the two formulations. The similarity factor (f 2) of the in vitro dissolution profiles was calculated. The geometric mean ratio (90% confidence interval) of tablet to capsule was 0.9680 (0.8873–1.0560) and 1.0322 (0.9359–1.1385) for C max and AUC last, respectively. The IIV of C max and AUC last of the tablet was smaller than the capsule. The f 2 values were >50 in all media. Both formulations were well tolerated. Thus, the tablet formulation of tacrolimus has smaller IIV in the systemic exposure than capsule, while having comparable PK and tolerability profiles, which may render it as a better treatment option for organ transplant patients.

          Most cited references21

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          Chemistry and biology of the immunophilins and their immunosuppressive ligands.

          Cyclosporin A, FK506, and rapamycin are inhibitors of specific signal transduction pathways that lead to T lymphocyte activation. These immunosuppressive agents bind with high affinity to cytoplasmic receptors termed immunophilins (immunosuppressant binding proteins). Studies in this area have focused on the structural basis for the molecular recognition of immunosuppressants by immunophilins and the biological consequences of their interactions. Defining the biological roles of this emerging family of receptors and their ligands may illuminate the process of protein trafficking in cells and the mechanisms of signal transmission through the cytoplasm.
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            In vitro dissolution profile comparison--statistics and analysis of the similarity factor, f2.

            To describe the properties of the similarity factor (f2) as a measure for assessing the similarity of two dissolution profiles. Discuss the statistical properties of the estimate based on sample means. The f2 metrics and the decision rule is evaluated using examples of dissolution profiles. The confidence interval is calculated using bootstrapping method. The bias of the estimate using sample mean dissolution is evaluated. 1. f2 values were found to be sensitive to number of sample points, after the dissolution plateau has been reached. 2. The statistical evaluation of f2 could be made using 90% confidence interval approach. 3. The statistical distribution of f2 metrics could be simulated using 'Bootstrap' method. A relatively robust distribution could be obtained after more than 500 'Bootstraps'. 4. A statistical 'bias correction' was found to reduce the bias. The similarity factor f2 is a simple measure for the comparison of two dissolution profiles. But the commonly used similarity factor estimate f2 is a biased and conservative estimate of f2. The bootstrap approach is a useful tool to simulate the confidence interval.
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              Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract.

              The rate-limiting step to absorption of drugs from the gastrointestinal (GI) tract is often dissolution from the dosage form. Consideration of the Noyes-Whitney dissolution model shows that drug diffusivity, solubility in the gastrointestinal contents, the surface area of the solid wetted by the lumenal fluids and the GI hydrodynamics all play a role in determining the in vivo dissolution rate. Solubility in the GI contents is determined by aqueous solubility, crystalline form, drug lipophilicity, solubilization by native surfactants and co-ingested foodstuffs, and pK(a) in relation to the GI pH profile. Compounds with aqueous solubilities lower than 100 microg/ml often present dissolution limitations to absorption. The dose:solubility ratio of the drug provides an estimate of the volume of fluids required to dissolve an individual dose, and when this volume exceeds 1 l, dissolution is often problematic. The surface area of a drug available for dissolution depends on the particle size of the solid and its ability to be wetted by lumenal fluids. Other physiological factors that can play a role in dissolution include the viscosity of the lumenal contents, through its effect on the diffusivity, and mixing and flow patterns within the gut. In order to better predict in vivo dissolution of drugs, dissolution tests which more adequately simulate the physiological conditions are needed.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                28 September 2017
                : 11
                : 2861-2869
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul
                [2 ]Clinical Trial Center, Ajou University Medical Center, Suwon
                [3 ]Research Institute, Chong Kun Dang Pharmaceutical Corp, Yongin
                [4 ]Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Republic of Korea
                Author notes
                Correspondence: Howard Lee, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, 145 Gwanggyo-ro, Yeongtong-gu, Suwon 16229, Gyeonggi, Republic of Korea, Tel +82 31 888 9157, Fax +82 2 742 9252, Email howardlee@ 123456snu.ac.kr
                © 2017 Kim et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                new formulation,incrementally modified drug,comparative pharmacokinetics,healthy volunteers,immunosuppressant


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