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Pharmaceutics
Special Issues
Development of Physiologically Based Pharmacokinetic (PBPK) Modeling
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Development of Physiologically Based Pharmacokinetic (PBPK) Modeling

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

Deadline for manuscript submissions: 31 May 2025 | Viewed by 11489

Special Issue Editors

Dr. Bárbara Sánchez-Dengra

E-Mail Website
Guest Editor
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain
Interests: blood-brain barrier; bioequivalence; in vivo predictive dissolution; in vitro-in vivo correlation; PBPK; pharmacokinetics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Isabel Gonzalez-Alvarez

E-Mail Website
Guest Editor
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain
Interests: PBPK; biowaivers; pharmacokinetics; dissolution; absorption; drug solubility
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue: “Development of Physiologically Based Pharmacokinetic (PBPK) Modeling”. PBPK modeling is a mathematical tool which is able to describe the drug concentration in an organism using compartments that correspond to the different tissues and taking into consideration the physiology of this organism to parameterize the model.

This type of model has become useful in drug development since its discovery and early phases, when in vitro data and physicochemical properties could be used to obtain plasma profiles, which would be, later on, validated in vivo, until the clinical development phases, in which simulations can be used to describe drug performance in special populations.

This Special Issue aims to compile the latest research carried out with this tool, in both preclinical and clinical development stages. Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: early drug development, risk assessment and toxicity assessment, absorption/formulation modeling, and the prediction of drug–disease interactions and drug–drug interactions.

We look forward to receiving your contributions.

Dr. Bárbara Sánchez-Dengra
Prof. Dr. Isabel Gonzalez-Alvarez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • physiologically based pharmacokinetic modeling (PBPK)
  • modeling and simulations (M&S)
  • pharmacokinetics
  • ADME
  • pharmacometrics

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Published Papers (5 papers)

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Research

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18 pages, 4761 KiB  
Article
Whole-Body Physiologically Based Pharmacokinetic Modeling Framework for Tissue Target Engagement of CD3 Bispecific Antibodies
by Monica E. Susilo, Stephan Schaller, Luis David Jiménez-Franco, Alexander Kulesza, Wilhelmus E. A. de Witte, Shang-Chiung Chen, C. Andrew Boswell, Danielle Mandikian and Chi-Chung Li
Pharmaceutics 2025, 17(4), 500; https://doi.org/10.3390/pharmaceutics17040500 - 9 Apr 2025
Viewed by 682
Abstract
Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy [...] Read more.
Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy in solid tumors. Optimizing biodistribution is key to overcoming these challenges. Methods: A physiologically based pharmacokinetic (PBPK) model was developed that incorporates T-cell transmigration, retention, receptor binding, receptor turnover, and cellular engagement. Preclinical biodistribution data were modeled using two TCB formats: one lacking tumor target binding and another with target arm binding, each with varying CD3 affinities in a transgenic tumor-bearing mouse model. Results: The PBPK model successfully described the distribution of activated T-cells and various TCB formats. It accurately predicted preclinical biodistribution patterns, demonstrating that higher CD3 affinity leads to faster clearance from the blood and increased accumulation in T-cell-rich organs, often reducing tumor exposure. Simulations of HER2-CD3 TCB doses (0.1 µg to 100 mg) revealed monotonic increases in synapse AUC within the tumor. A bell-shaped dose-Cmax relationship for synapse formation was observed, and Tmax was delayed at higher doses. Blood PK was a reasonable surrogate for tumor synapse at low doses but less predictive at higher doses. Conclusions: We developed a whole-body PBPK model to simulate the biodistribution of T-cells and TCB molecules. The insights from this model provide a comprehensive understanding of the factors affecting PK, synapse formation, and TCB activity, aiding in dose optimization and the design of effective therapeutic strategies. Full article
(This article belongs to the Special Issue Development of Physiologically Based Pharmacokinetic (PBPK) Modeling)
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17 pages, 4537 KiB  
Article
Development and Application of Physiologically-Based Pharmacokinetic Model to Predict Systemic and Organ Exposure of Colorectal Cancer Drugs
by Sara Peribañez-Dominguez, Zinnia Parra-Guillen and Iñaki F. Troconiz
Pharmaceutics 2025, 17(1), 57; https://doi.org/10.3390/pharmaceutics17010057 - 3 Jan 2025
Viewed by 1246
Abstract
Background/Objectives: Colorectal cancer (CRC) holds the third and second position among cancers affecting men and women, respectively. Frequently, the first-line treatment for metastatic CRC consists of the intravenous administration of 5-fluorouracil and leucovorin in combination with oxaliplatin or irinotecan. Physiologically-based pharmacokinetic models (PBPK) [...] Read more.
Background/Objectives: Colorectal cancer (CRC) holds the third and second position among cancers affecting men and women, respectively. Frequently, the first-line treatment for metastatic CRC consists of the intravenous administration of 5-fluorouracil and leucovorin in combination with oxaliplatin or irinotecan. Physiologically-based pharmacokinetic models (PBPK) aim to mechanistically incorporate body physiology and drug physicochemical attributes, enabling the description of both systemic and organ drug exposure based on the treatment specificities. This bottom-up approach represents an opportunity to personalize treatment and minimize the therapeutic risk/benefit ratio through the understanding of drug distribution within colorectal tissue. This project has the goal of characterizing the systemic and tissue exposure of four anti-cancer drugs in humans using a PBPK platform fed with data from the literature. Methods: A literature search was performed to collect clinical data on systemic concentration versus time profiles. Physicochemical features were obtained from the literature, as well as parameters associated with distribution, metabolism, and excretion. The PBPK models were built using PK-Sim®. Results: The data from 51 clinical studies were extracted and combined in one single dataset. The PBPK models successfully described the exposure vs. time profiles with respect to both, with both the typical tendency and dispersion shown by the data. The percentage of observations falling within the two-fold error bounds ranged between 94 and 100%. The colon/plasma AUCinf ratios were similar for 5-FU, oxaliplatin, and leucovorin, but it was significantly higher for irinotecan. Conclusions: The PBPK models support tailored treatment approaches by linking in vitro studies to organ exposure. These models serve as the initial step towards incorporating a dedicated tumor compartment, which will further account for the variability in tumor microenvironment characteristics to improve therapeutic strategies. Full article
(This article belongs to the Special Issue Development of Physiologically Based Pharmacokinetic (PBPK) Modeling)
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26 pages, 1294 KiB  
Article
PBPK Modeling of Lamotrigine and Efavirenz during Pregnancy: Implications for Personalized Dosing and Drug-Drug Interaction Management
by Bárbara Costa, Maria João Gouveia and Nuno Vale
Pharmaceutics 2024, 16(9), 1163; https://doi.org/10.3390/pharmaceutics16091163 - 3 Sep 2024
Cited by 3 | Viewed by 1816
Abstract
This study aimed to model the pharmacokinetics of lamotrigine (LTG) and efavirenz (EFV) in pregnant women using physiologically based pharmacokinetic (PBPK) and pregnancy-specific PBPK (p-PBPK) models. For lamotrigine, the adult PBPK model demonstrated accurate predictions for pharmacokinetic parameters. Predictions for the area under [...] Read more.
This study aimed to model the pharmacokinetics of lamotrigine (LTG) and efavirenz (EFV) in pregnant women using physiologically based pharmacokinetic (PBPK) and pregnancy-specific PBPK (p-PBPK) models. For lamotrigine, the adult PBPK model demonstrated accurate predictions for pharmacokinetic parameters. Predictions for the area under the curve (AUC) and peak plasma concentration (Cmax) generally agreed well with observed values. During pregnancy, the PBPK model accurately predicted AUC and Cmax with a prediction error (%PE) of less than 25%. The evaluation of the EFV PBPK model revealed mixed results. While the model accurately predicted certain parameters for non-pregnant adults, significant discrepancies were observed in predictions for higher doses (600 vs. 400 mg) and pregnant individuals. The model’s performance during pregnancy was poor, indicating the need for further refinement to account for genetic polymorphism. Gender differences also influenced EFV pharmacokinetics, with lower exposure levels in females compared to males. These findings highlight the complexity of modeling EFV, in general, but specifically in pregnant populations, and the importance of validating such models for accurate clinical application. The study highlights the importance of tailoring dosing regimens for pregnant individuals to ensure both safety and efficacy, particularly when using combination therapies with UGT substrate drugs. Although drug-drug interactions between LTG and EFV appear minimal, further research is needed to improve predictive models and enhance their accuracy. Full article
(This article belongs to the Special Issue Development of Physiologically Based Pharmacokinetic (PBPK) Modeling)
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21 pages, 3654 KiB  
Article
Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood–Brain Barrier and Assess Target Site Disposition
by Parsshava Mehta, Amira Soliman, Leyanis Rodriguez-Vera, Stephan Schmidt, Paula Muniz, Monica Rodriguez, Marta Forcadell, Emili Gonzalez-Perez and Valvanera Vozmediano
Pharmaceutics 2024, 16(2), 226; https://doi.org/10.3390/pharmaceutics16020226 - 4 Feb 2024
Cited by 5 | Viewed by 3345
Abstract
The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood–brain barrier (BBB) permeability evaluation tools are needed to explore drugs’ ability to access the CNS. An outstanding aspect of physiologically based [...] Read more.
The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood–brain barrier (BBB) permeability evaluation tools are needed to explore drugs’ ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution. We aimed to qualify a PBPK platform model to be used as a tool to predict CNS concentrations when significant transporter activity is absent and human data are sparse or unavailable. Data from the literature on the plasma and CNS of rats and humans regarding acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam were collected. Human BBB permeability values were extrapolated from rats using inter-species differences in BBB surface area. The percentage of predicted AUC and Cmax within the 1.25-fold criterion was 85% and 100% for rats and humans, respectively, with an overall GMFE of <1.25 in all cases. This work demonstrated the successful application of the PBPK platform for predicting human CNS concentrations of drugs passively crossing the BBB. Future applications include the selection of promising CNS drug candidates and the evaluation of new posologies for existing drugs. Full article
(This article belongs to the Special Issue Development of Physiologically Based Pharmacokinetic (PBPK) Modeling)
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Review

Jump to: Research

18 pages, 2121 KiB  
Review
Advancements in Virtual Bioequivalence: A Systematic Review of Computational Methods and Regulatory Perspectives in the Pharmaceutical Industry
by Nasser Alotaiq and Doni Dermawan
Pharmaceutics 2024, 16(11), 1414; https://doi.org/10.3390/pharmaceutics16111414 - 3 Nov 2024
Cited by 3 | Viewed by 3086
Abstract
Background/Objectives: The rise of virtual bioequivalence studies has transformed the pharmaceutical landscape, enabling more efficient drug development processes. This systematic review aims to explore advancements in physiologically based pharmacokinetic (PBPK) modeling, its regulatory implications, and its role in achieving virtual bioequivalence, particularly for [...] Read more.
Background/Objectives: The rise of virtual bioequivalence studies has transformed the pharmaceutical landscape, enabling more efficient drug development processes. This systematic review aims to explore advancements in physiologically based pharmacokinetic (PBPK) modeling, its regulatory implications, and its role in achieving virtual bioequivalence, particularly for complex drug formulations. Methods: We conducted a systematic review of clinical trials using computational methods, particularly PBPK modeling, to carry out bioequivalence assessments. Eligibility criteria are emphasized during in silico modeling and pharmacokinetic simulations. Comprehensive literature searches were performed across databases such as PubMed, Scopus, and the Cochrane Library. A search strategy using key terms and Boolean operators ensured that extensive coverage was achieved. We adhered to the PRISMA guidelines in regard to the study selection, data extraction, and quality assessment, focusing on key characteristics, methodologies, outcomes, and regulatory perspectives from the FDA and EMA. Results: Our findings indicate that PBPK modeling significantly enhances the prediction of pharmacokinetic profiles, optimizing dosing regimens, while minimizing the need for extensive clinical trials. Regulatory agencies have recognized this utility, with the FDA and EMA developing frameworks to integrate in silico methods into drug evaluations. However, challenges such as study heterogeneity and publication bias may limit the generalizability of the results. Conclusions: This review highlights the critical need for standardized protocols and robust regulatory guidelines to facilitate the integration of virtual bioequivalence methodologies into pharmaceutical practices. By embracing these advancements, the pharmaceutical industry can improve drug development efficiency and patient outcomes, paving the way for innovative therapeutic solutions. Continued research and adaptive regulatory frameworks will be essential in navigating this evolving field. Full article
(This article belongs to the Special Issue Development of Physiologically Based Pharmacokinetic (PBPK) Modeling)
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