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Pharmaceutics
Special Issues
Recent Application of Pharmacokinetics in Drug Development and Drug Therapy
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Recent Application of Pharmacokinetics in Drug Development and Drug Therapy

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (10 November 2019) | Viewed by 38182

Special Issue Editors

Prof. Dr. Yong-Bok Lee

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Guest Editor
College of Pharmacy and Institute of Bioequivalence and Bridging Study, Chonnam National University, 77 Yongbong-ro, Buk-Gu, Gwangju 61186, Republic of Korea
Interests: pharmacometrics; modeling; nanoformulation; drug delivery; lymph; herbal medicine; clinical study
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hea-Young Cho

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Guest Editor
College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Korea
Interests: biopharmaceutics; physiologically based pharmacokinetics; pharmacokinetics; drug interaction; population pharmacokinetics; pharmacogenetics; regulatory sciences

Special Issue Information

Dear Colleagues,

A better understanding of pharmacokinetics (PKs) associated drug responses is essential to optimize drug development processes and drug therapy. To date, there has been growing interest in the use of advanced PKs for the determination of dosing strategies in new drug development. Moreover, with interest in personalized medicine, advanced PKs are expected to play a more important role in drug therapy as well as in drug development. Recent studies related to PKs have extended beyond the calculation of traditional PK parameters to PK modeling, PK/PD modeling, physiologically based pharmacokinetic (PBPK) modeling, population approach, and in vitro and in vivo correlation. These are represented by model-informed drug development (MIDD), which allows to reflect complex demographical, environmental, and pathophysiological conditions into the dosing regimen. This Special Issue on “Recent Application of Pharmacokinetics in Drug Development and Drug Therapy” will cover a wide range of topics, including but not limited to PKs, pharmacogenomics, biopharmaceutics, population PKs, PBPK modeling, drug interactions, and related disciplines.

Prof. Dr. Yong-Bok Lee
Prof. Dr. Hea-Young Cho
Guest Editors

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Keywords

  • Pharmacokinetics
  • PK/PD modeling
  • Biopharmaceutics
  • Population pharmacokinetics
  • Drug interactions
  • PBPK model
  • In vitro and in vivo correlation

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Published Papers (7 papers)

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Research

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16 pages, 4153 KiB  
Article
High Molecular Weight Chitosan-Complexed RNA Nanoadjuvant for Effective Cancer Immunotherapy
by Jin Joo Choi, Quoc-Viet Le, Dongho Kim, Young Bong Kim, Gayong Shim and Yu-Kyoung Oh
Pharmaceutics 2019, 11(12), 680; https://doi.org/10.3390/pharmaceutics11120680 - 14 Dec 2019
Cited by 19 | Viewed by 4475
Abstract
Nucleic acid-based adjuvants have recently emerged as promising candidates for use in cancer vaccines to induce tumor-suppressing immune cells. In this study, we tested whether complexation of a nucleic acid-based adjuvant with chitosan (CTS) modulates immune adjuvant functions. As a nucleic acid-based adjuvant, [...] Read more.
Nucleic acid-based adjuvants have recently emerged as promising candidates for use in cancer vaccines to induce tumor-suppressing immune cells. In this study, we tested whether complexation of a nucleic acid-based adjuvant with chitosan (CTS) modulates immune adjuvant functions. As a nucleic acid-based adjuvant, we used toll-like receptor 3-recognizing RNA adjuvant (RA). Negatively charged RA formed nanoscale polyplexes with cationic CTS that possessed positive zeta potentials. RA/CTS polyplexes exerted dendritic cell (DC)-maturation effects without causing significant DC toxicity. This DC-maturation effect was CTS molecular weight dependent, with RA/CTS polyplexes with a CTS molecular weight of 340 kDa (RA/CTS 340K) producing the greatest effect. Subcutaneous injection of RA/CTS 340K polyplexes with the model tumor antigen ovalbumin exerted a preventive effect against challenge by ovalbumin-expressing tumor cells. It also provided greater inhibitory effects against a second challenge with the same tumor cells compared with other treatments. These protective effects of subcutaneous RA/CTS polyplex treatment were associated with the highest tumor antigen-specific humoral and cellular immune responses after tumor challenge, and with the greatest infiltration of CD4 helper T cell and CD8 T cell into the tumor tissues. Mice vaccinated with ovalbumin and RA/CTS polyplexes showed complete survival, even after repeated challenge with tumor cells. Our results suggest the potential of RA/CTS polyplexes as effective nanoadjuvants in the design of tumor vaccines and cancer immunotherapy. Full article
(This article belongs to the Special Issue Recent Application of Pharmacokinetics in Drug Development and Drug Therapy)
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15 pages, 2299 KiB  
Article
Population Pharmacokinetics of Cis-, Trans-, and Total Cefprozil in Healthy Male Koreans
by Ji-Hun Jang, Seung-Hyun Jeong, Hea-Young Cho and Yong-Bok Lee
Pharmaceutics 2019, 11(10), 531; https://doi.org/10.3390/pharmaceutics11100531 - 14 Oct 2019
Cited by 13 | Viewed by 5073
Abstract
Cefprozil, one of cephalosporin antibiotics, has been used extensively in clinics. However, pharmacokinetic (PK) information on cefprozil is still very limited. There have been no reports of population pharmacokinetics (PPKs). A PPK model for cefprozil will be a great advantage for clinical use. [...] Read more.
Cefprozil, one of cephalosporin antibiotics, has been used extensively in clinics. However, pharmacokinetic (PK) information on cefprozil is still very limited. There have been no reports of population pharmacokinetics (PPKs). A PPK model for cefprozil will be a great advantage for clinical use. Thus, the aim of this study was to develop a PPK model for cefprozil for healthy male Koreans. Clinical PK and demographic data of healthy Korean males receiving cefprozil at a dose of 1000 mg were analyzed using Phoenix® NLME™. A one-compartment model with first-order absorption with lag-time was constructed as a base model. The model was extended to include covariates that influenced between-subject variability. Creatinine clearance significantly influenced systemic clearance of cefprozil. The final PPK model for cis-, trans-, and total cefprozil was established and validated. PPK parameter values of cis- and total cefprozil were similar to each other, but different from those of trans-isomer. Herein, we describe the establishment of accurate PPK models of cis-, trans-, and total cefprozil for healthy male Koreans for the first time. It may be useful as a dosing algorithm for the general population. These results might also contribute to the development of stereoisomeric cefprozil. Full article
(This article belongs to the Special Issue Recent Application of Pharmacokinetics in Drug Development and Drug Therapy)
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8 pages, 819 KiB  
Article
Pharmacokinetic Study of NADPH Oxidase Inhibitor Ewha-18278, a Pyrazole Derivative
by Seul Gee Lee, Jaeok Lee, Kyung Min Kim, Kee-In Lee, Yun Soo Bae and Hwa Jeong Lee
Pharmaceutics 2019, 11(9), 482; https://doi.org/10.3390/pharmaceutics11090482 - 17 Sep 2019
Cited by 7 | Viewed by 3950
Abstract
In a previous study, the specific NOX1/2/4 inhibitor Ewha-18278 was confirmed as a possible treatment for osteoporosis both in vitro and in vivo. Here, we investigated the pharmacokinetics (PK) of the compound by intravenous (IV) and oral administrations to rats. Dimethyl sulfoxide (DMSO)-based [...] Read more.
In a previous study, the specific NOX1/2/4 inhibitor Ewha-18278 was confirmed as a possible treatment for osteoporosis both in vitro and in vivo. Here, we investigated the pharmacokinetics (PK) of the compound by intravenous (IV) and oral administrations to rats. Dimethyl sulfoxide (DMSO)-based and diazepam injection-based formulations were used to dissolve the compound. In the latter formulation applicable to humans, the changes in PK parameters were monitored at two different concentrations (1 mg/mL and 2 mg/mL). The area under the plasma concentration-time curve from zero time to infinity (AUCinf) of Ewha-18278 was highest in the DMSO-based formulation (2 mg/mL). Also, the concentration was increased 1.6-fold at the low concentration of the diazepam injection-based formulation compared to the high concentration. There was no statistical significance in the AUCinf of the compound between DMSO-based formulation (2 mg/mL) and diazepam injection-based formulation (1 mg/mL). These results suggest that Ewha-18278 can be delivered to humans by both IV and oral routes. In addition, the diazepam injection-based formulation of Ewha-18278 appears to be a suitable candidate for dosage development for future toxicity test and clinical trial. Full article
(This article belongs to the Special Issue Recent Application of Pharmacokinetics in Drug Development and Drug Therapy)
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13 pages, 2222 KiB  
Article
Physicochemical, Pharmacokinetic, and Toxicity Evaluation of Methoxy Poly(ethylene glycol)-b-Poly(d,l-Lactide) Polymeric Micelles Encapsulating Alpinumisoflavone Extracted from Unripe Cudrania tricuspidata Fruit
by Min Jeong Jo, Yang Hee Jo, Yu Jin Lee, Chun-Woong Park, Jin-Seok Kim, Jin Tae Hong, Youn Bok Chung, Mi Kyeong Lee and Dae Hwan Shin
Pharmaceutics 2019, 11(8), 366; https://doi.org/10.3390/pharmaceutics11080366 - 1 Aug 2019
Cited by 24 | Viewed by 4291
Abstract
Alpinumisoflavone, a major compound in unripe Cudrania tricuspidata fruit is reported to exhibit numerous beneficial pharmacological activities, such as osteoprotective, antibacterial, estrogenic, anti-metastatic, atheroprotective, antioxidant, and anticancer effects. Despite its medicinal value, alpinumisoflavone is poorly soluble in water, which makes it difficult to [...] Read more.
Alpinumisoflavone, a major compound in unripe Cudrania tricuspidata fruit is reported to exhibit numerous beneficial pharmacological activities, such as osteoprotective, antibacterial, estrogenic, anti-metastatic, atheroprotective, antioxidant, and anticancer effects. Despite its medicinal value, alpinumisoflavone is poorly soluble in water, which makes it difficult to formulate and administer intravenously (i.v.). To overcome these limitations, we used methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-b-PLA) polymeric micelles to solubilize alpinumisoflavone and increase its bioavailability, and evaluated their toxicity in vivo. Alpinumisoflavone-loaded polymeric micelles were prepared using thin-film hydration method, and their physicochemical properties were characterized for drug release, particle size, drug-loading (DL, %), and encapsulation efficiency (EE, %). The in vitro drug release profile was determined and the release rate of alpinumisoflavone from mPEG-b-PLA micelles was slower than that from drug solution, and sustained. Pharmacokinetic studies showed decreased total clearance and volume of distribution of alpinumisoflavone, whereas area under the curve (AUC) and bioavailability were significantly increased by incorporation in mPEG-b-PLA micelles. In vivo toxicity assay revealed that alpinumisoflavone-loaded mPEG-b-PLA micelles had no severe toxicity. In conclusion, we prepared an intravenous (i.v.) injectable alpinumisoflavone formulation, which was solubilized using mPEG-b-PLA micelles, and determined their physicochemical properties, pharmacokinetics, and toxicity profiles. Full article
(This article belongs to the Special Issue Recent Application of Pharmacokinetics in Drug Development and Drug Therapy)
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12 pages, 2065 KiB  
Article
Application of Size and Maturation Functions to Population Pharmacokinetic Modeling of Pediatric Patients
by Hyun-moon Back, Jong Bong Lee, Nayoung Han, Sungwoo Goo, Eben Jung, Junyeong Kim, Byungjeong Song, Sook Hee An, Jung Tae Kim, Sandy Jeong Rhie, Yoon Sun Ree, Jung-woo Chae, JaeWoo Kim and Hwi-yeol Yun
Pharmaceutics 2019, 11(6), 259; https://doi.org/10.3390/pharmaceutics11060259 - 3 Jun 2019
Cited by 21 | Viewed by 4166
Abstract
Traditionally, dosage for pediatric patients has been optimized using simple weight-scaled methods, but these methods do not always meet the requirements of children. To overcome this discrepancy, population pharmacokinetic (PK) modeling of size and maturation functions has been proposed. The main objective of [...] Read more.
Traditionally, dosage for pediatric patients has been optimized using simple weight-scaled methods, but these methods do not always meet the requirements of children. To overcome this discrepancy, population pharmacokinetic (PK) modeling of size and maturation functions has been proposed. The main objective of the present study was to evaluate a new modeling method for pediatric patients using clinical data from three different clinical studies. To develop the PK models, a nonlinear mixed effect modeling method was employed, and to explore PK differences in pediatric patients, size with allometric and maturation with Michaelis–Menten type functions were evaluated. Goodness of fit plots, visual predictive check and bootstrap were used for model evaluation. Single application of size scaling to PK parameters was statistically significant for the over one year old group. On the other hand, simultaneous use of size and maturation functions was statistically significant for infants younger than one year old. In conclusion, population PK modeling for pediatric patients was successfully performed using clinical data. Size and maturation functions were applied according to established criteria, and single use of size function was applicable for over one year ages, while size and maturation functions were more effective for PK analysis of neonates and infants. Full article
(This article belongs to the Special Issue Recent Application of Pharmacokinetics in Drug Development and Drug Therapy)
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Review

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11 pages, 1164 KiB  
Review
Noninvasive Assessment of Exosome Pharmacokinetics In Vivo: A Review
by Do Hee Kim, Vinoth Kumar Kothandan, Hye Won Kim, Ki Seung Kim, Ji Young Kim, Hyeon Jin Cho, Yong-kyu Lee, Dong-Eun Lee and Seung Rim Hwang
Pharmaceutics 2019, 11(12), 649; https://doi.org/10.3390/pharmaceutics11120649 - 3 Dec 2019
Cited by 32 | Viewed by 5037
Abstract
Exosomes, intraluminal vesicles that contain informative DNA, RNA, proteins, and lipid membranes derived from the original donor cells, have recently been introduced to therapy and diagnosis. With their emergence as an alternative to cell therapy and having undergone clinical trials, proper analytical standards [...] Read more.
Exosomes, intraluminal vesicles that contain informative DNA, RNA, proteins, and lipid membranes derived from the original donor cells, have recently been introduced to therapy and diagnosis. With their emergence as an alternative to cell therapy and having undergone clinical trials, proper analytical standards for evaluating their pharmacokinetics must now be established. Molecular imaging techniques such as fluorescence imaging, magnetic resonance imaging, and positron emission tomography (PET) are helpful to visualizing the absorption, distribution, metabolism, and excretion of exosomes. After exosomes labelled with a fluorescer or radioisotope are administered in vivo, they are differentially distributed according to the characteristics of each tissue or lesion, and real-time biodistribution of exosomes can be noninvasively monitored. Quantitative analysis of exosome concentration in biological fluid or tissue samples is also needed for the clinical application and industrialization of exosomes. In this review, we will discuss recent pharmacokinetic applications to exosomes, including labelling methods for in vivo imaging and analytical methods for quantifying exosomes, which will be helpful for evaluating pharmacokinetics of exosomes and improving exosome development and therapy. Full article
(This article belongs to the Special Issue Recent Application of Pharmacokinetics in Drug Development and Drug Therapy)
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22 pages, 1002 KiB  
Review
Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration
by Laura García-Quintanilla, Andrea Luaces-Rodríguez, María Gil-Martínez, Cristina Mondelo-García, Olalla Maroñas, Víctor Mangas-Sanjuan, Miguel González-Barcia, Irene Zarra-Ferro, Pablo Aguiar, Francisco J. Otero-Espinar and Anxo Fernández-Ferreiro
Pharmaceutics 2019, 11(8), 365; https://doi.org/10.3390/pharmaceutics11080365 - 31 Jul 2019
Cited by 99 | Viewed by 10236
Abstract
Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with [...] Read more.
Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance. Full article
(This article belongs to the Special Issue Recent Application of Pharmacokinetics in Drug Development and Drug Therapy)
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