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Pharmaceutics
Special Issues
Approaches to Individualized Drug Therapy Based on Population Pharmacometrics
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Approaches to Individualized Drug Therapy Based on Population Pharmacometrics

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 15087

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
Dr. Seung-Hyun Jeong

E-Mail Website
Guest Editor
College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon-si 57922, Jeollanam-do, Republic of Korea
Interests: pharmacokinetics; pharmacodynamics; toxicometrics; risk assessment; physiologically based modeling; lymphatic delivery; nanoformulation and evaluation; bioanalytical method development and validation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pharmacometrics modeling plays a leading role in the journey towards personalized therapy by quantitatively predicting the correlations of the various factors influencing changes in drug behavior in in vivo systems. The demand for physiologically based pharmacokinetic–pharmacodynamic modeling techniques, including those for the pharmacokinetic–pharmacodynamic modeling of whole populations, is increasing in the pharmaceutical and clinical industries, with the ultimate aim of improving effects through optimal drug therapy. Pharmacometrics modeling is clearly an important tool in drug development and for the development of effective clinical applications.

The purpose of this Special Issue is to collect approaches to individualized drug therapy based on population pharmacometrics. This issue will not be limited to population modeling, but will also include work on the prediction of drug behavior through mathematical modeling and model simulations. In addition, extended application studies on model-based clinical dosing systems and regimens are also welcome. This Special Issue is an opportunity to move one step closer to precision medicine based on quantitative modeling techniques.

Prof. Dr. Yong-Bok Lee
Dr. Seung-Hyun Jeong
Guest Editors

Manuscript Submission Information

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Keywords

  • population pharmacokinetics
  • population pharmacodynamics
  • physiologically based modeling
  • model simulation
  • precision medicine
  • dosage regimen
  • clinical study

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Published Papers (7 papers)

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18 pages, 3601 KiB  
Article
Toward Personalized Salbutamol Therapy: Validating Virtual Patient-Derived Population Pharmacokinetic Model with Real-World Data
by Lara Marques and Nuno Vale
Pharmaceutics 2024, 16(7), 881; https://doi.org/10.3390/pharmaceutics16070881 - 30 Jun 2024
Viewed by 1143
Abstract
Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. [...] Read more.
Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. Herein, we developed a popPK model for salbutamol, a short-acting β2-agonist (SABA) used in asthma treatment, to identify key patient characteristics that influence treatment response. To do so, synthetic data from physiologically-based pharmacokinetic (PBPK) models was employed, followed by an external validation using real patient data derived from an equivalent study. Thirty-two virtual patients were included in this study. A two-compartment model, with first-order absorption (no delay), and linear elimination best fitted our data, according to diagnostic plots and selection criteria. External validation demonstrated a strong agreement between individual predicted and observed values. The incorporation of covariates into the basic structural model identified a significant impact of age on clearance (Cl) and intercompartmental clearance (Q); gender on Cl and the constant rate of absorption (ka); race on Cl; and weight on Cl in the volume of distribution of the peripheral compartment (V2). This study addresses critical challenges in popPK modeling, particularly data scarcity, incompleteness, and homogeneity, in traditional clinical trials, by leveraging synthetic data from PBPK modeling. Significant associations between individual characteristics and salbutamol’s PK parameters, here uncovered, highlight the importance of personalized therapeutic regimens for optimal treatment outcomes. Full article
(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)
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26 pages, 4460 KiB  
Article
A Physiologically Based Pharmacokinetic (PBPK) Study to Assess the Adjuvanticity of Three Peptides in an Oral Vaccine
by Leonor Saldanha, Ülo Langel and Nuno Vale
Pharmaceutics 2024, 16(6), 780; https://doi.org/10.3390/pharmaceutics16060780 - 8 Jun 2024
Viewed by 853
Abstract
Following up on the first PBPK model for an oral vaccine built for alpha-tocopherol, three peptides are explored in this article to verify if they could support an oral vaccine formulation as adjuvants using the same PBPK modeling approach. A literature review was [...] Read more.
Following up on the first PBPK model for an oral vaccine built for alpha-tocopherol, three peptides are explored in this article to verify if they could support an oral vaccine formulation as adjuvants using the same PBPK modeling approach. A literature review was conducted to verify what peptides have been used as adjuvants in the last decades, and it was noticed that MDP derivatives have been used, with one of them even being commercially approved and used as an adjuvant when administered intravenously in oncology. The aim of this study was to build optimized models for three MDP peptides (MDP itself, MTP-PE, and murabutide) and to verify if they could act as adjuvants for an oral vaccine. Challenges faced by peptides in an oral delivery system are taken into consideration, and improvements to the formulations to achieve better results are described in a step-wise approach to reach the most-optimized model. Once simulations are performed, results are compared to determine what would be the best peptide to support as an oral adjuvant. According to our results, MTP-PE, the currently approved and commercialized peptide, could have potential to be incorporated into an oral formulation. It would be interesting to proceed with further in vivo experiments to determine the behavior of this peptide when administered orally with a proper formulation to overcome the challenges of oral delivery systems. Full article
(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)
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12 pages, 4569 KiB  
Article
Safety Evaluation and Population Pharmacokinetics of Camostat Mesylate and Its Major Metabolites Using a Phase I Study
by Gwanyoung Kim, Hyun-ki Moon, Taeheon Kim, So-hye Yun, Hwi-yeol Yun, Jang Hee Hong and Dae-Duk Kim
Pharmaceutics 2023, 15(9), 2357; https://doi.org/10.3390/pharmaceutics15092357 - 21 Sep 2023
Viewed by 1397
Abstract
Camostat mesylate is expected to be promising as a treatment option for COVID-19, in addition to other indications for which it is currently used. Furthermore, in vitro experiments have confirmed the potential of camostat and its metabolites to be effective against COVID-19. Therefore, [...] Read more.
Camostat mesylate is expected to be promising as a treatment option for COVID-19, in addition to other indications for which it is currently used. Furthermore, in vitro experiments have confirmed the potential of camostat and its metabolites to be effective against COVID-19. Therefore, clinical trials were conducted to evaluate the safety and pharmacokinetic characteristics of camostat after single-dose administration. Additionally, we aim to predict the pharmacokinetics of repeated dosing through modeling and simulation based on clinical trials. Clinical trials were conducted on healthy Korean adults, and an analysis was carried out of the metabolites of camostat, GBPA, and GBA. Pharmacokinetic modeling and simulation were performed using Monolix. There were no safety issues (AEs, physical examinations, clinical laboratory tests, vital sign measurements, and ECG) during the clinical trial. The pharmacokinetic characteristics at various doses were identified. It was confirmed that AUC last and Cmax increased in proportion to dose in both GBPA and GBA, and linearity was also confirmed in log-transformed power model regression. Additionally, the accumulation index was predicted (1.12 and 1.08 for GBPA and GBA). The pharmacokinetics of camostat for various dose administrations and indications can be predicted prior to clinical trials using the developed camostat model. Furthermore, it can be used for various indications by connecting it with pharmacodynamic information. Full article
(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)
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17 pages, 3817 KiB  
Article
Application of Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung and Trachea Exposure of Pyronaridine and Artesunate in Hamsters
by Dong Wook Kang, Kyung Min Kim, Ju Hee Kim and Hea-Young Cho
Pharmaceutics 2023, 15(3), 838; https://doi.org/10.3390/pharmaceutics15030838 - 3 Mar 2023
Cited by 4 | Viewed by 3261
Abstract
A fixed-dose combination of pyronaridine and artesunate, one of the artemisinin-based combination therapies, has been used as a potent antimalarial treatment regimen. Recently, several studies have reported the antiviral effects of both drugs against severe acute respiratory syndrome coronavirus two (SARS-CoV-2). However, there [...] Read more.
A fixed-dose combination of pyronaridine and artesunate, one of the artemisinin-based combination therapies, has been used as a potent antimalarial treatment regimen. Recently, several studies have reported the antiviral effects of both drugs against severe acute respiratory syndrome coronavirus two (SARS-CoV-2). However, there are limited data on the pharmacokinetics (PKs), lung, and trachea exposures that could be correlated with the antiviral effects of pyronaridine and artesunate. The purpose of this study was to evaluate the pharmacokinetics, lung, and trachea distribution of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) using a minimal physiologically-based pharmacokinetic (PBPK) model. The major target tissues for evaluating dose metrics are blood, lung, and trachea, and the nontarget tissues were lumped together into the rest of the body. The predictive performance of the minimal PBPK model was evaluated using visual inspection between observations and model predictions, (average) fold error, and sensitivity analysis. The developed PBPK models were applied for the multiple-dosing simulation of daily oral pyronaridine and artesunate. A steady state was reached about three to four days after the first dosing of pyronaridine and an accumulation ratio was calculated to be 1.8. However, the accumulation ratio of artesunate and dihydroartemisinin could not be calculated since the steady state of both compounds was not achieved by daily multiple dosing. The elimination half-life of pyronaridine and artesunate was estimated to be 19.8 and 0.4 h, respectively. Pyronaridine was extensively distributed to the lung and trachea with the lung-to-blood and trachea-to-blood concentration ratios (=Cavg,tissue/Cavg,blood) of 25.83 and 12.41 at the steady state, respectively. Also, the lung-to-blood and trachea-to-blood AUC ratios for artesunate (dihydroartemisinin) were calculated to be 3.34 (1.51) and 0.34 (0.15). The results of this study could provide a scientific basis for interpreting the dose–exposure–response relationship of pyronaridine and artesunate for COVID-19 drug repurposing. Full article
(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)
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16 pages, 2530 KiB  
Article
Parent-Metabolite Pharmacokinetic Modeling of Formononetin and Its Active Metabolites in Rats after Oral Administration of Formononetin Formulations
by Ju Hee Kim, Dong Wook Kang, Seok-jin Cho and Hea-Young Cho
Pharmaceutics 2023, 15(1), 45; https://doi.org/10.3390/pharmaceutics15010045 - 23 Dec 2022
Cited by 5 | Viewed by 2105
Abstract
Formononetin is a major isoflavone contained in propolis and is reported to exhibit various pharmacological effects. However, the use of formononetin in pharmaceutical industry is limited due to its low bioavailability and solubility. There had been several efforts on formononetin formulation development, but [...] Read more.
Formononetin is a major isoflavone contained in propolis and is reported to exhibit various pharmacological effects. However, the use of formononetin in pharmaceutical industry is limited due to its low bioavailability and solubility. There had been several efforts on formononetin formulation development, but further study is required to acquire optimal formulation. The aim of this study is to conduct pharmacokinetic (PK) evaluations after the oral administration of three formononetin formulations (20 mg/kg) in male Sprague Dawley rats. Then, a parent-metabolite PK model for formononetin was developed and evaluated for the first time. To do this, a simultaneous analysis method for formononetin and its active metabolites, daidzein, dihydrodaidzein and equol in rat plasma was developed using ultra-performance liquid chromatography tandem mass spectrometry. The separation was performed using a gradient elution of water and acetonitrile and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 µm particle size) at a temperature of 30 ± 5 °C. The simultaneous analytical method developed in this study was validated according to international guidance and was successfully applied for the pharmacokinetic study. The time-plasma concentrations of formononetin and daidzein were well described by a two-compartment model combined with a metabolite compartment. Additionally, plasma protein binding assay was conducted in male rat plasma. The findings from the study could be used as a fundamental for the future development of formononetin as a pharmaceutical product. Full article
(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)
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27 pages, 3324 KiB  
Article
Torsemide Pharmacometrics in Healthy Adult Populations Including CYP2C9 Genetic Polymorphisms and Various Patient Groups through Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling
by Seung-Hyun Jeong, Ji-Hun Jang and Yong-Bok Lee
Pharmaceutics 2022, 14(12), 2720; https://doi.org/10.3390/pharmaceutics14122720 - 5 Dec 2022
Cited by 1 | Viewed by 2878
Abstract
Torsemide is a widely used diuretic in clinical practice. In this study, pharmacokinetic (PK) and pharmacodynamic (PD) simulations of torsemide for various population groups and exposure scenarios were performed through human-scale physiologically-based PK-PD (PBPK-PD) modeling of torsemide. For PBPK-PD modeling of torsemide, invitro [...] Read more.
Torsemide is a widely used diuretic in clinical practice. In this study, pharmacokinetic (PK) and pharmacodynamic (PD) simulations of torsemide for various population groups and exposure scenarios were performed through human-scale physiologically-based PK-PD (PBPK-PD) modeling of torsemide. For PBPK-PD modeling of torsemide, invitro and clinical data of torsemide reported previously were used. After exposure to clinical doses of torsemide, observed plasma (or serum) concentration and urine torsemide excretion profiles were used as PK-data, and observed urinary sodium excretion rate was used as PD-data. The model was then extended to take into account physiological and biochemical factors according to different CYP2C9 phenotypes or patient populations. The established model captured various torsemide clinical results well. Differences in torsemide PKs and PDs between patient groups or CYP2C9 genetic polymorphisms were modelologically identified. It was confirmed that degrees of differences in torsemide PKs and PDs by disease groups were greater than those according to different CYP2C9 phenotypes. According to torsemide administration frequency or dose change, it was confirmed that although the difference in plasma PKs between groups (healthy adult and patient groups) could increase to 14.80 times, the difference in PDs was reduced to 1.01 times. Results of this study suggested that it is very important to consider disease groups in the setting of torsemide clinical therapy and that it is difficult to predict PD proportionally with only differences in PKs of torsemide between population groups. The PBPK-PD model established in this study is expected to be utilized for various clinical cases involving torsemide application in the future, enabling optimal drug therapy. Full article
(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)
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24 pages, 2302 KiB  
Systematic Review
Is a Lower Dose of Rivaroxaban Required for Asians? A Systematic Review of a Population Pharmacokinetics and Pharmacodynamics Analysis of Rivaroxaban
by Xiao-Qin Liu, Zi-Ran Li, Chen-Yu Wang, Yue-Ting Chen and Zheng Jiao
Pharmaceutics 2023, 15(2), 588; https://doi.org/10.3390/pharmaceutics15020588 - 9 Feb 2023
Cited by 10 | Viewed by 2479
Abstract
Rivaroxaban has been widely used to prevent and treat various thromboembolic diseases for more than a decade. However, whether a lower dose of rivaroxaban is required for Asians is still debatable. This review aimed to explore the potential ethnic difference in pharmacokinetic/pharmacodynamic (PK/PD) [...] Read more.
Rivaroxaban has been widely used to prevent and treat various thromboembolic diseases for more than a decade. However, whether a lower dose of rivaroxaban is required for Asians is still debatable. This review aimed to explore the potential ethnic difference in pharmacokinetic/pharmacodynamic (PK/PD) characteristics between Asians and Caucasians. A systematic search was conducted and twenty-four studies were identified, of which 10 were conducted on Asian adults, 11 on predominantly Caucasian adults, and 3 on Caucasian pediatrics. The apparent clearance (CL/F) of rivaroxaban in Caucasian adults with non-valvular atrial fibrillation (6.45–7.64 L/h) was about 31–43% higher than that in Asians (4.46–5.98 L/h) taking 10~20 mg rivaroxaban every 24 h. Moreover, there was no obvious difference in CL/F among Japanese, Chinese, Thai, and Irani people. Regarding PK/PD relationship, prothrombin time was linked to rivaroxaban concentration in a linear or near-linear manner, and Factor Xa activity was linked with the Emax model. The exposure–response relationship was comparable between Asians and Caucasians. Renal function has a significant influence on CL/F, and no covariate was recognized for exposure–response relationship. In conclusion, a lower dose of rivaroxaban might be required for Asians, and further studies are warranted to verify this ethnic difference to facilitate optimal dosing regimens. Full article
(This article belongs to the Special Issue Approaches to Individualized Drug Therapy Based on Population Pharmacometrics)
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