Physiologically-Based Pharmacokinetics (PBPK) and Biopharmaceutics (PBBM) 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 2021) | Viewed by 18298

Special Issue Editors

Department of Pharmacy and Pharmaceutical Technology and Parasitology, School of Pharmacy, University of Valencia, Valencia, Spain
Interests: pharmacokinetics; biopharmaceutics; bioavailability; oral absorption
Department of Pharmacy and Pharmaceutical Technology and Parasitology, School of Pharmacy, University of Valencia, Valencia, Spain
Interests: pharmacokinetics; biopharmaceutics; oral absorption; topical formulations; in vitro release
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacy and Pharmaceutical Technology and Parasitology, School of Pharmacy, University of Valencia, Valencia, Spain
Interests: pharmacokinetics; biopharmaceutics; oral absorption; dissolution methods
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Physiologically based pharmacokinetic (PBPK) modelling as a valuable tool for model informed drug discovery and development process, gaining recognition by the main regulatory authorities for drug approval because of their strength in data integration, mechanistic perspective and superior predictive power. Physiologically based biopharmaceutic (PBBM) models cover a recent field of research by the integration of in vitro dissolution experiments into PBPK models to predict the behaviour of the oral formulation in vivo and verifying whether the dissolution method of the pharmaceutical product is biopredictive or clinically relevant. Both model-informed strategies (PBPK and PBBM) contribute to optimise the drug development and use of medicines.

The aim of this Special Issue is to highlight recent advances in all aspects relevant to PBPK and PBBM modelling from the early drug discovery to beyond phase III clinical trials as well as its application in the clinic aimed at achieving an optimal dosage regimen. Additionally, regulatory and academic applications showing the impact in drug’s approval and solving theoretical aspects using PBPK or PBBM models are also welcome.

Dr. Matilde Merino-Sanjuán
Dr. Virginia Merino Sanjuán
Dr. Victor Mangas Sanjuán
Guest Editors

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Keywords

  • physiologically based pharmacokinetic modelling
  • physiologically based biopharmaceutic modeling
  • oral absorption
  • clinically relevant dissolution specifications
  • dissolution modelling

Published Papers (5 papers)

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Research

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17 pages, 2978 KiB  
Article
Physiologically Based Pharmacokinetic (PBPK) Model of Gold Nanoparticle-Based Drug Delivery System for Stavudine Biodistribution
by Hinojal Zazo, Clara I. Colino, Carmen Gutiérrez-Millán, Andres A. Cordero, Matthias Bartneck and José M. Lanao
Pharmaceutics 2022, 14(2), 406; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020406 - 13 Feb 2022
Cited by 6 | Viewed by 2216
Abstract
Computational modelling has gained attention for evaluating nanoparticle-based drug delivery systems. Physiologically based pharmacokinetic (PBPK) modelling provides a mechanistic approach for evaluating drug biodistribution. The aim of this work is to develop a specific PBPK model to simulate stavudine biodistribution after the administration [...] Read more.
Computational modelling has gained attention for evaluating nanoparticle-based drug delivery systems. Physiologically based pharmacokinetic (PBPK) modelling provides a mechanistic approach for evaluating drug biodistribution. The aim of this work is to develop a specific PBPK model to simulate stavudine biodistribution after the administration of a 40 nm gold nanoparticle-based drug delivery system in rats. The model parameters used have been obtained from literature, in vitro and in vivo studies, and computer optimization. Based on these, the PBPK model was built, and the compartments included were considered as permeability rate-limited tissues. In comparison with stavudine solution, a higher biodistribution of stavudine into HIV reservoirs and the modification of pharmacokinetic parameters such as the mean residence time (MRT) have been observed. These changes are particularly noteworthy in the liver, which presents a higher partition coefficient (from 0.27 to 0.55) and higher MRT (from 1.28 to 5.67 h). Simulated stavudine concentrations successfully describe these changes in the in vivo study results. The average fold error of predicted concentrations after the administration of stavudine-gold nanoparticles was within the 0.5–2-fold error in all of the tissues. Thus, this PBPK model approach may help with the pre-clinical extrapolation to other administration routes or the species of stavudine gold nanoparticles. Full article
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13 pages, 2401 KiB  
Article
A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice
by Nouran R. R. Zaid, Peter Kletting, Gordon Winter, Vikas Prasad, Ambros J. Beer and Gerhard Glatting
Pharmaceutics 2021, 13(12), 2132; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122132 - 10 Dec 2021
Cited by 9 | Viewed by 3072
Abstract
In vivo alpha particle generators have great potential for the treatment of neuroendocrine tumors in alpha-emitter-based peptide receptor radionuclide therapy (α-PRRT). Quantitative pharmacokinetic analyses of the in vivo alpha particle generator and its radioactive decay products are required to address concerns about the [...] Read more.
In vivo alpha particle generators have great potential for the treatment of neuroendocrine tumors in alpha-emitter-based peptide receptor radionuclide therapy (α-PRRT). Quantitative pharmacokinetic analyses of the in vivo alpha particle generator and its radioactive decay products are required to address concerns about the efficacy and safety of α-PRRT. A murine whole-body physiologically based pharmacokinetic (PBPK) model was developed for 212Pb-labeled somatostatin analogs (212Pb-SSTA). The model describes pharmacokinetics of 212Pb-SSTA and its decay products, including specific and non-specific glomerular and tubular uptake. Absorbed dose coefficients (ADC) were calculated for bound and unbound radiolabeled SSTA and its decay products. Kidneys received the highest ADC (134 Gy/MBq) among non-target tissues. The alpha-emitting 212Po contributes more than 50% to absorbed doses in most tissues. Using this model, it is demonstrated that α-PRRT based on 212Pb-SSTA results in lower absorbed doses in non-target tissue than α-PRRT based on 212Bi-SSTA for a given kidneys absorbed dose. In both approaches, the energies released in the glomeruli and proximal tubules account for 54% and 46%, respectively, of the total energy absorbed in kidneys. The 212Pb-SSTA-PBPK model accelerates the translation from bench to bedside by enabling better experimental design and by improving the understanding of the underlying mechanisms. Full article
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20 pages, 2923 KiB  
Article
Pharmacokinetics and Pharmacodynamics of T-Cell Bispecifics in the Tumour Interstitial Fluid
by Miro Julian Eigenmann, Tine Veronica Karlsen, Marek Wagner, Olav Tenstad, Tina Weinzierl, Tanja Fauti, Hans Peter Grimm, Trude Skogstrand, Christian Klein, Johannes Sam, Pablo Umana, Marina Bacac, Helge Wiig and Antje-Christine Walz
Pharmaceutics 2021, 13(12), 2105; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122105 - 07 Dec 2021
Cited by 5 | Viewed by 3101
Abstract
The goal of this study is to investigate the pharmacokinetics in plasma and tumour interstitial fluid of two T-cell bispecifics (TCBs) with different binding affinities to the tumour target and to assess the subsequent cytokine release in a tumour-bearing humanised mouse model. Pharmacokinetics [...] Read more.
The goal of this study is to investigate the pharmacokinetics in plasma and tumour interstitial fluid of two T-cell bispecifics (TCBs) with different binding affinities to the tumour target and to assess the subsequent cytokine release in a tumour-bearing humanised mouse model. Pharmacokinetics (PK) as well as cytokine data were collected in humanised mice after iv injection of cibisatamab and CEACAM5-TCB which are binding with different binding affinities to the tumour antigen carcinoembryonic antigen (CEA). The PK data were modelled and coupled to a previously published physiologically based PK model. Corresponding cytokine release profiles were compared to in vitro data. The PK model provided a good fit to the data and precise estimation of key PK parameters. High tumour interstitial concentrations were observed for both TCBs, influenced by their respective target binding affinities. In conclusion, we developed a tailored experimental method to measure PK and cytokine release in plasma and at the site of drug action, namely in the tumour. Integrating those data into a mathematical model enabled to investigate the impact of target affinity on tumour accumulation and can have implications for the PKPD assessment of the therapeutic antibodies. Full article
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15 pages, 1517 KiB  
Article
A Physiologically-Based Pharmacokinetic (PBPK) Model Network for the Prediction of CYP1A2 and CYP2C19 Drug–Drug–Gene Interactions with Fluvoxamine, Omeprazole, S-mephenytoin, Moclobemide, Tizanidine, Mexiletine, Ethinylestradiol, and Caffeine
by Tobias Kanacher, Andreas Lindauer, Enrica Mezzalana, Ingrid Michon, Celine Veau, Jose David Gómez Mantilla, Valerie Nock and Angèle Fleury
Pharmaceutics 2020, 12(12), 1191; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121191 - 08 Dec 2020
Cited by 16 | Viewed by 4245
Abstract
Physiologically-based pharmacokinetic (PBPK) modeling is a well-recognized method for quantitatively predicting the effect of intrinsic/extrinsic factors on drug exposure. However, there are only few verified, freely accessible, modifiable, and comprehensive drug–drug interaction (DDI) PBPK models. We developed a qualified whole-body PBPK DDI network [...] Read more.
Physiologically-based pharmacokinetic (PBPK) modeling is a well-recognized method for quantitatively predicting the effect of intrinsic/extrinsic factors on drug exposure. However, there are only few verified, freely accessible, modifiable, and comprehensive drug–drug interaction (DDI) PBPK models. We developed a qualified whole-body PBPK DDI network for cytochrome P450 (CYP) CYP2C19 and CYP1A2 interactions. Template PBPK models were developed for interactions between fluvoxamine, S-mephenytoin, moclobemide, omeprazole, mexiletine, tizanidine, and ethinylestradiol as the perpetrators or victims. Predicted concentration–time profiles accurately described a validation dataset, including data from patients with genetic polymorphisms, demonstrating that the models characterized the CYP2C19 and CYP1A2 network over the whole range of DDI studies investigated. The models are provided on GitHub (GitHub Inc., San Francisco, CA, USA), expanding the library of publicly available qualified whole-body PBPK models for DDI predictions, and they are thereby available to support potential recommendations for dose adaptations, support labeling, inform the design of clinical DDI trials, and potentially waive those. Full article
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Review

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19 pages, 678 KiB  
Review
Current Evidence, Challenges, and Opportunities of Physiologically Based Pharmacokinetic Models of Atorvastatin for Decision Making
by Javier Reig-López, Alfredo García-Arieta, Víctor Mangas-Sanjuán and Matilde Merino-Sanjuán
Pharmaceutics 2021, 13(5), 709; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13050709 - 13 May 2021
Cited by 9 | Viewed by 2963
Abstract
Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation [...] Read more.
Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation in special sub-groups of the population, leading to regulatory recognition. Several PBPK models of ATS have been published in the recent years, addressing different aspects of the PK properties of ATS. Therefore, the aims of this review are (i) to summarize the physicochemical and pharmacokinetic characteristics involved in the time-course of ATS, and (ii) to evaluate the major highlights and limitations of the PBPK models of ATS published so far. The PBPK models incorporate common elements related to the physicochemical aspects of ATS. However, there are important differences in relation to the analyte evaluated, the type and effect of transporters and metabolic enzymes, and the permeability value used. Additionally, this review identifies major processes (lactonization, P-gp contribution, ATS-Ca solubility, simultaneous management of multiple analytes, and experimental evidence in the target population), which would enhance the PBPK model prediction to serve as a valid tool for ATS dose optimization. Full article
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