Pharmacometrics Research for the Realization and Advancement of Precision Medicine

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (25 August 2024) | Viewed by 5740

Special Issue Editors


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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

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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

Special Issue Information

Dear Colleagues,

The contribution of medicine in overcoming human diseases is great and, as a result, human health and lifespan have been greatly increased. Drugs for the treatment of various diseases are continuously being developed, and formulation research is progressing at a remarkable speed. However, in the reality that most medicines rely on empirical usage and apply uniformly to all people, preparing effective alternatives and ways to overcome this has become a very important concern. Precision medicine and individualized drug therapy are very important research areas, as important as drug development for effective clinical application through reductions in side effects and maximization of drug efficacy.

This Special Issue focuses on the application and current status of pharmacometric studies for the realization and advancement of precision medicine. Therefore, pharmacokinetics, pharmacodynamics, in vivo drug quantification, and genetic polymorphism studies (such as enzymes or transporters involved in drug absorption, distribution, metabolism, and excretion) for precision medicine and individualized pharmacotherapy settings will be suitable for this Special Issue scope. In addition, studies on predicting drug behavior and efficacy in the body through mathematical modeling, exploring clinical usage based on models, and exploring effective covariates to explain the diversity of pharmacokinetics and pharmacodynamics among individuals will be very welcome. Finally, it is expected that a lot of useful and interesting research information for the realization of precision medicine will be introduced in this Special Issue.

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

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Keywords

  • precision medicine
  • individualized therapy
  • pharmacometrics
  • mathematical modeling
  • quantitative prediction
  • regimen setting
  • drug-response variability

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Published Papers (3 papers)

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Research

11 pages, 1579 KiB  
Article
Guidance on Selecting Optimal Steady-State Tacrolimus Concentrations for Continuous IV Perfusion: Insights from Physiologically Based Pharmacokinetic Modeling
by Romain Martischang, Argyro Nikolaou, Youssef Daali, Caroline Flora Samer and Jean Terrier
Pharmaceuticals 2024, 17(8), 1047; https://doi.org/10.3390/ph17081047 - 8 Aug 2024
Viewed by 1124
Abstract
Introduction: The dose–response relationships of tacrolimus have been primarily assessed through trough concentrations during intermittent administrations. In scenarios where oral administration (PO) is unfeasible, continuous intravenous (IV) administration is advised. Under these circumstances, only steady-state (Css) plasma or blood concentrations are measured, [...] Read more.
Introduction: The dose–response relationships of tacrolimus have been primarily assessed through trough concentrations during intermittent administrations. In scenarios where oral administration (PO) is unfeasible, continuous intravenous (IV) administration is advised. Under these circumstances, only steady-state (Css) plasma or blood concentrations are measured, with the absence of distinct trough levels (Cmin). Consequently, the measured concentrations are frequently misinterpreted as trough concentrations, potentially resulting in sub-therapeutic true tacrolimus blood levels. This study employs physiologically based pharmacokinetic modeling (PBPK) to establish the Css/Cmin ratio for tacrolimus across various clinical scenarios. Method: Using a validated PBPK model, the tacrolimus dose (both PO and IV) and the Css/Cmin ratios corresponding to matching area under the blood concentration–time curve during a dosage interval (AUCτ) values were estimated under different conditions, including healthy subjects and individuals exhibiting cytochrome P450 3A (CYP3A) interactions or CYP3A5 polymorphisms, along with a demonstration of a real-life clinical application. Result: In healthy volunteers, the oral/intravenous (PO/IV) dose ratio was found to be 4.25, and the Css/Cmin ratio was 1.40. A specific clinical case substantiated the practical applicability of the Css/Cmin ratio as simulated by PBPK, demonstrating no immediate clinical complications related to the transplant. When considering liver donors versus recipients expressing CYP3A5, the tacrolimus AUCτ was notably affected, yielding a PO/IV dose ratio of 4.00 and a Css/Cmin ratio of 1.75. Furthermore, the concomitant administration of the CYP3A inhibitor itraconazole given PO resulted in a PO/IV ratio of 1.75 with and a Css/Cmin ratio of 1.28. Notably, the inhibitory effect of itraconazole was diminished when administered IV. Conclusions: Through the application of PBPK methodologies, this study estimates the PO/IV dose ratios and Css/Cmin ratios that can enhance dose adjustment and therapeutic drug monitoring during the switch between IV and PO administration of tacrolimus in transplant patients, ultimately guiding clinicians in real-time decision-making. Further validation with in vivo data is recommended to support these findings. Full article
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15 pages, 1685 KiB  
Article
A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment
by Mahnoor Pasha, Ammara Zamir, Muhammad Fawad Rasool, Hamid Saeed, Tanveer Ahmad, Nawaf Shalih Alqahtani, Lamya Saif Alqahtani and Faleh Alqahtani
Pharmaceuticals 2024, 17(7), 924; https://doi.org/10.3390/ph17070924 - 10 Jul 2024
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Abstract
Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly [...] Read more.
Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration–time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients. Full article
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16 pages, 3771 KiB  
Article
Population Pharmacokinetic Modeling of Zaltoprofen in Healthy Adults: Exploring the Dosage Regimen
by Ji-Hun Jang, Seung-Hyun Jeong and Yong-Bok Lee
Pharmaceuticals 2023, 16(2), 161; https://doi.org/10.3390/ph16020161 - 22 Jan 2023
Cited by 2 | Viewed by 1906
Abstract
Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to [...] Read more.
Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications. Full article
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