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Special Issue "Approaches to Individualized Drug Therapy Based on Population Pharmacometrics"

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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 4311

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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

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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

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Keywords

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

Published Papers (4 papers)

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Open AccessArticle

Application of Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung and Trachea Exposure of Pyronaridine and Artesunate in Hamsters

and

Pharmaceutics 2023, 15(3), 838; https://doi.org/10.3390/pharmaceutics15030838 - 03 Mar 2023

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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 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 (=C_avg,tissue/C_avg,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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Open AccessArticle

Parent-Metabolite Pharmacokinetic Modeling of Formononetin and Its Active Metabolites in Rats after Oral Administration of Formononetin Formulations

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Pharmaceutics 2023, 15(1), 45; https://doi.org/10.3390/pharmaceutics15010045 - 23 Dec 2022

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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 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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Open AccessArticle

Torsemide Pharmacometrics in Healthy Adult Populations Including CYP2C9 Genetic Polymorphisms and Various Patient Groups through Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling

Seung-Hyun Jeong

Ji-Hun Jang

and

Yong-Bok Lee

Pharmaceutics 2022, 14(12), 2720; https://doi.org/10.3390/pharmaceutics14122720 - 05 Dec 2022

Cited by 1 | Viewed by 798

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 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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Open AccessSystematic Review

Is a Lower Dose of Rivaroxaban Required for Asians? A Systematic Review of a Population Pharmacokinetics and Pharmacodynamics Analysis of Rivaroxaban

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Pharmaceutics 2023, 15(2), 588; https://doi.org/10.3390/pharmaceutics15020588 - 09 Feb 2023

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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) 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 E_max 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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