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Pharmaceutics
Special Issues
New Insights into Physiologically Based Pharmacokinetic Modeling
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New Insights into Physiologically Based Pharmacokinetic Modeling

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

Deadline for manuscript submissions: closed (10 November 2024) | Viewed by 3852

Special Issue Editor

Dr. Zubida M. Al-Majdoub

E-Mail Website
Guest Editor
Centre for Applied Pharmacokinetic Research, The University of Manchester, Manchester, UK
Interests: physiologically based pharmacokinetic; endogenous compounds; biomarker

Special Issue Information

Dear Colleagues,

Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique for predicting the absorption, distribution, metabolism, and excretion (ADME) of synthetic or natural chemical substances in humans and other animal species. PBPK modeling is used in pharmaceutical research and drug development.

PBPK models are compartmental models like many others, but they have a few advantages over so-called "classical" pharmacokinetic models, which are less grounded in physiology. PBPK models can first be used to abstract and eventually reconcile disparate data (from physicochemical or biochemical experiments, in vitro or in vivo pharmacological or toxicological experiments, etc.) They also provide access to internal body concentrations of chemicals or their metabolites, and in particular, the site of their effects can be therapeutic or toxic.

This Special Issue is dedicated to new, cutting-edge examples of the application of PBPK modeling to show its versatility and highlight recent advances in the field. Modeling scientists are cordially invited to share their research covering the full spectrum of PBPK modeling and simulation, including (but not limited to) the pharmacokinetics of special populations (e.g., geriatrics, pediatrics, pregnancy, ICU), the modeling of pathophysiology (e.g., renal impairment, hepatic impairment), drug–gene interactions, drug–drug interactions, the integration of tissue concentration (e.g., by imaging techniques), PBPK covariate modeling, PBPK-based precision dosing, PBPK/PD modeling, PBPK-based Quantitative Systems Pharmacology (QSP) approaches or technical advances.

Dr. Zubida M. Al-Majdoub
Guest Editor

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 (PBPK) modeling
  • drug–drug interactions
  • drug–gene interactions
  • PBPK-based precision dosing
  • PBPK-based Quantitative Systems Pharmacology

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Published Papers (3 papers)

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Research

22 pages, 2970 KiB  
Article
Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework
by Aneesh V. Karkhanis, Matthew D. Harwood, Felix Stader, Frederic Y. Bois and Sibylle Neuhoff
Pharmaceutics 2024, 16(10), 1284; https://doi.org/10.3390/pharmaceutics16101284 - 30 Sep 2024
Viewed by 1018
Abstract
Background/Objectives: Plasma levels of 4β-hydroxycholesterol (4β-OHC), a CYP3A-specific metabolite of cholesterol, are elevated after administration of CYP3A inducers like rifampicin and carbamazepine. To simulate such plasma 4β-OHC increase, we developed a physiologically based pharmacokinetic (PBPK) model of cholesterol and 4β-OHC in the Simcyp [...] Read more.
Background/Objectives: Plasma levels of 4β-hydroxycholesterol (4β-OHC), a CYP3A-specific metabolite of cholesterol, are elevated after administration of CYP3A inducers like rifampicin and carbamazepine. To simulate such plasma 4β-OHC increase, we developed a physiologically based pharmacokinetic (PBPK) model of cholesterol and 4β-OHC in the Simcyp PBPK Simulator (Version 23, Certara UK Ltd.) using a middle-out approach. Methods: Relevant physicochemical properties and metabolic pathway data for CYP3A and CYP27A1 was incorporated in the model. Results: The PBPK model recovered the observed baseline plasma 4β-OHC levels in Caucasian, Japanese, and Korean populations. The model also captured the higher baseline 4β-OHC levels in females compared to males, indicative of sex-specific differences in CYP3A abundance. More importantly, the model recapitulated the increased 4β-OHC plasma levels after multiple-dose rifampicin treatment in six independent studies, indicative of hepatic CYP3A induction. The verified model also captured the altered 4β-OHC levels in CYP3A4/5 polymorphic populations and with other CYP3A inducers. The model is limited by scant data on relative contributions of CYP3A and CYP27A1 pathways and does not account for regulatory mechanisms that control plasma cholesterol and 4β-OHC levels. Conclusion: This study provides a quantitative fit-for-purpose and framed-for-future modelling framework for an endogenous biomarker to evaluate the DDI risk with hepatic CYP3A induction. Full article
(This article belongs to the Special Issue New Insights into Physiologically Based Pharmacokinetic Modeling)
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17 pages, 2000 KiB  
Article
Physiologically-Based Pharmacokinetic Modeling and In Vitro–In Vivo Correlation of TV-46000 (Risperidone LAI): Prediction from Dog to Human
by David Bibi, Raphael Bilgraer, Lilach Steiner and Hussein Hallak
Pharmaceutics 2024, 16(7), 896; https://doi.org/10.3390/pharmaceutics16070896 - 4 Jul 2024
Viewed by 919
Abstract
The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in [...] Read more.
The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in adults. Following sc injection, the copolymers together with risperidone precipitate to form a sc depot under the skin to deliver therapeutic levels of risperidone over a prolonged period of either 1 month or 2 months, depending upon the dose. This work presents the strategy and the results of the physiologically-based pharmacokinetic (PBPK) modeling and establishing of in vitro–in vivo correlation (IVIVC) for the prediction of TV-46000 pharmacokinetic profile in humans, using in vitro release, intravenous (iv), and sc single-dose pharmacokinetic data in beagle dogs. The resulting simulated TV-46000 PK profile in humans showed that the shape of the predicted risperidone and its active metabolite 9-OH-risperidone PK profiles was different from the observed one, thus suggesting that the TV-46000 release profile was species-dependent and cannot be directly extrapolated from dog to human. In conclusion, while level A IVIVC cannot be claimed, this work combining PBPK and IVIVC modeling represents an interesting alternative approach for complex injectable formulations where classical methods are not applicable. Full article
(This article belongs to the Special Issue New Insights into Physiologically Based Pharmacokinetic Modeling)
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15 pages, 1678 KiB  
Article
Can 3D Printed Tablets Be Bioequivalent and How to Test It: A PBPK Model Based Virtual Bioequivalence Study for Ropinirole Modified Release Tablets
by Olha Shuklinova, Gabriela Wyszogrodzka-Gaweł, Ewelina Baran, Bartosz Lisowski, Barbara Wiśniowska, Przemysław Dorożyński, Piotr Kulinowski and Sebastian Polak
Pharmaceutics 2024, 16(2), 259; https://doi.org/10.3390/pharmaceutics16020259 - 9 Feb 2024
Cited by 1 | Viewed by 1313
Abstract
As the field of personalized dosing develops, the pharmaceutical manufacturing industry needs to offer flexibility in terms of tailoring the drug release and strength to the individual patient’s needs. One of the promising tools which have such capacity is 3D printing technology. However, [...] Read more.
As the field of personalized dosing develops, the pharmaceutical manufacturing industry needs to offer flexibility in terms of tailoring the drug release and strength to the individual patient’s needs. One of the promising tools which have such capacity is 3D printing technology. However, manufacturing small batches of drugs for each patient might lead to huge test burden, including the need to conduct bioequivalence trials of formulations to support the change of equipment or strength. In this paper we demonstrate how to use 3D printing in conjunction with virtual bioequivalence trials based on physiologically based pharmacokinetic (PBPK) modeling. For this purpose, we developed 3D printed ropinirole formulations and tested their bioequivalence with the reference product Polpix. The Simcyp simulator and previously developed ropinirole PBPK model were used for the clinical trial simulations. The Weibull-fitted dissolution profiles of test and reference formulations were used as inputs for the model. The virtual bioequivalence trials were run using parallel design. The study power of 80% was reached using 125 individuals. The study demonstrated how to use PBPK modeling in conjunction with 3D printing to test the virtual bioequivalence of newly developed formulations. This virtual experiment demonstrated the bioequivalence of one of the newly developed formulations with a reference product available on a market. Full article
(This article belongs to the Special Issue New Insights into Physiologically Based Pharmacokinetic Modeling)
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