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Article ; Online: Mathematical modeling of mammalian circadian clocks affecting drug and disease responses.

Mavroudis, Panteleimon D / Jusko, William J

Journal of pharmacokinetics and pharmacodynamics

2021 Volume 48, Issue 3, Page(s) 375–386

Abstract: To align with daily environmental changes, most physiological processes in mammals exhibit a time-of-day rhythmicity. This circadian control of physiology is intrinsically driven by a cell-autonomous clock gene network present in almost all cells of the ... ...

Abstract	To align with daily environmental changes, most physiological processes in mammals exhibit a time-of-day rhythmicity. This circadian control of physiology is intrinsically driven by a cell-autonomous clock gene network present in almost all cells of the body that drives rhythmic expression of genes that regulate numerous molecular and cellular processes. Accordingly, many aspects of pharmacology and toxicology also oscillate in a time-of-day manner giving rise to diverse effects on pharmacokinetics and pharmacodynamics. Genome-wide studies and mathematical modeling are available tools that have significantly improved our understanding of these nonlinear aspects of physiology and therapeutics. In this manuscript current literature and our prior work on the model-based approaches that have been used to explore circadian genomic systems of mammals are reviewed. Such basic understanding and having an integrative approach may provide new strategies for chronotherapeutic drug treatments and yield new insights for the restoration of the circadian system when altered by diseases.
MeSH term(s)	Animals ; Chronopharmacokinetics ; Circadian Clocks/physiology ; Drug Chronotherapy ; Humans ; Models, Biological
Language	English
Publishing date	2021-03-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-021-09746-z
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Article ; Online: A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics.

Patidar, Krutika / Pillai, Nikhil / Dhakal, Saroj / Avery, Lindsay B / Mavroudis, Panteleimon D

Journal of pharmacokinetics and pharmacodynamics

2024

Abstract: Protein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship ... ...

Abstract	Protein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship between the physicochemical properties and PK is still largely unknown. In this work we present a minimal physiologically-based pharmacokinetic (mPBPK) model that incorporates a multivariate quantitative relation between a therapeutic's physicochemical parameters and its corresponding ADME properties. The model's compound-specific input includes molecular weight, molecular size (Stoke's radius), molecular charge, binding affinity to FcRn, and specific antigen affinity. Through derived and fitted empirical relationships, the model demonstrates the effect of these compound-specific properties on antibody disposition in both plasma and peripheral tissues using observed PK data in mice and humans. The mPBPK model applies the two-pore hypothesis to predict size-based clearance and exposure of full-length antibodies (150 kDa) and antibody fragments (50-100 kDa) within a onefold error. We quantitatively relate antibody charge and PK parameters like uptake rate, non-specific binding affinity, and volume of distribution to capture the relatively faster clearance of positively charged mAb as compared to negatively charged mAb. The model predicts the terminal plasma clearance of slightly positively and negatively charged antibody in humans within a onefold error. The mPBPK model presented in this work can be used to predict the target-mediated disposition of a drug when compound-specific and target-specific properties are known. To our knowledge, a combined effect of antibody weight, size, charge, FcRn, and antigen has not been incorporated and studied in a single mPBPK model previously. By conclusively incorporating and relating a multitude of protein's physicochemical properties to observed PK, our mPBPK model aims to contribute as a platform approach in the early stages of drug development where many of these properties can be optimized to improve a molecule's PK and ultimately its efficacy.
Language	English
Publishing date	2024-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-023-09899-z
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Article ; Online: Machine Learning guided early drug discovery of small molecules.

Pillai, Nikhil / Dasgupta, Aparajita / Sudsakorn, Sirimas / Fretland, Jennifer / Mavroudis, Panteleimon D

Drug discovery today

2022 Volume 27, Issue 8, Page(s) 2209–2215

Abstract: Machine learning (ML) approaches have been widely adopted within the early stages of the drug discovery process, particularly within the context of small-molecule drug candidates. Despite this, the use of ML is still limited in the pharmacokinetic/ ... ...

Abstract	Machine learning (ML) approaches have been widely adopted within the early stages of the drug discovery process, particularly within the context of small-molecule drug candidates. Despite this, the use of ML is still limited in the pharmacokinetic/pharmacodynamic (PK/PD) application space. Here, we describe recent progress and the role of ML used in preclinical drug discovery. We summarize the advances and current strategies used to predict ADME (absorption, distribution, metabolism and, excretion) properties of small molecules based on their structures, and predict structures based on the desired properties for molecular screening and optimization. Finally, we discuss the use of ML to predict PK to rank the ability of drug candidates to achieve appropriate exposures and hence provide important insights into safety and efficacy.
MeSH term(s)	Drug Discovery ; Machine Learning
Language	English
Publishing date	2022-03-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2022.03.017
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Article ; Online: A multi-model approach to predict efficacious clinical dose for an anti-TGF-β antibody (GC2008) in the treatment of osteogenesis imperfecta.

Mavroudis, Panteleimon D / Pillai, Nikhil / Wang, Qingping / Pouzin, Clemence / Greene, Benjamin / Fretland, Jennifer

CPT: pharmacometrics & systems pharmacology

2022 Volume 11, Issue 11, Page(s) 1485–1496

Abstract: Osteogenesis imperfecta (OI) is a heterogeneous group of inherited bone dysplasias characterized by reduced skeletal mass and bone fragility. Although the primary manifestation of the disease involves the skeleton, OI is a generalized connective tissue ... ...

Abstract	Osteogenesis imperfecta (OI) is a heterogeneous group of inherited bone dysplasias characterized by reduced skeletal mass and bone fragility. Although the primary manifestation of the disease involves the skeleton, OI is a generalized connective tissue disorder that requires a multidisciplinary treatment approach. Recent studies indicate that application of a transforming growth factor beta (TGF-β) neutralizing antibody increased bone volume fraction (BVF) and strength in an OI mouse model and improved bone mineral density (BMD) in a small cohort of patients with OI. In this work, we have developed a multitiered quantitative pharmacology approach to predict human efficacious dose of a new anti-TGF-β antibody drug candidate (GC2008). This method aims to translate GC2008 pharmacokinetic/pharmacodynamic (PK/PD) relationship in patients, using a number of appropriate mathematical models and available preclinical and clinical data. Compartmental PK linked with an indirect PD effect model was used to characterize both pre-clinical and clinical PK/PD data and predict a GC2008 dose that would significantly increase BMD or BVF in patients with OI. Furthermore, a physiologically-based pharmacokinetic model incorporating GC2008 and the body's physiological properties was developed and used to predict a GC2008 dose that would decrease the TGF-β level in bone to that of healthy individuals. By using multiple models, we aim to reveal information for different aspects of OI disease that will ultimately lead to a more informed dose projection of GC2008 in humans. The different modeling efforts predicted a similar range of pharmacologically relevant doses in patients with OI providing an informed approach for an early clinical dose setting.
MeSH term(s)	Humans ; Mice ; Animals ; Osteogenesis Imperfecta/drug therapy ; Osteogenesis Imperfecta/metabolism ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/pharmacology ; Transforming Growth Factor beta/therapeutic use ; Bone Density ; Bone and Bones/metabolism ; Disease Models, Animal
Chemical Substances	Transforming Growth Factor beta
Language	English
Publishing date	2022-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12857
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Article ; Online: ATLAS mPBPK: A MATLAB-Based Tool for Modeling and Simulation of Minimal Physiologically-Based Pharmacokinetic Models.

Mavroudis, Panteleimon D / Ayyar, Vivaswath S / Jusko, William J

CPT: pharmacometrics & systems pharmacology

2019 Volume 8, Issue 8, Page(s) 557–566

Abstract: Minimal physiologically-based pharmacokinetic (mPBPK) models are frequently used to model plasma pharmacokinetic (PK) data and utilize and yield physiologically relevant parameters. Compared with classical compartment and whole-body physiologically-based ...

Abstract	Minimal physiologically-based pharmacokinetic (mPBPK) models are frequently used to model plasma pharmacokinetic (PK) data and utilize and yield physiologically relevant parameters. Compared with classical compartment and whole-body physiologically-based pharmacokinetic modeling approaches, mPBPK models maintain a structure of intermediate physiological complexity that can be adequately informed by plasma PK data. In this tutorial, we present a MATLAB-based tool for the modeling and simulation of mPBPK models (ATLAS mPBPK) of small and large molecules. This tool enables the users to perform the following: (i) PK data visualization, (ii) simulation, (iii) parameter optimization, and (iv) local sensitivity analysis of mPBPK models in a simple and efficient manner. In addition to the theoretical background and implementation of the different tool functionalities, this tutorial includes simulation and sensitivity analysis showcases of small and large molecules with and without target-mediated drug disposition.
Language	English
Publishing date	2019-07-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12441
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Article ; Online: On the unphysical hypotheses in pharmacokinetics and oral drug absorption: Time to utilize instantaneous rate coefficients instead of rate constants.

Mavroudis, Panteleimon D / Kosmidis, Kosmas / Macheras, Panos

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2019 Volume 130, Page(s) 137–146

Abstract: This work aims to explore the unphysical assumptions associated with i) the homogeneity of the well mixed compartments of pharmacokinetics and ii) the diffusion limited model of drug dissolution. To this end, we i) tested the homogeneity hypothesis using ...

Abstract	This work aims to explore the unphysical assumptions associated with i) the homogeneity of the well mixed compartments of pharmacokinetics and ii) the diffusion limited model of drug dissolution. To this end, we i) tested the homogeneity hypothesis using Monte Carlo simulations for a reaction and a diffusional process that take place in Euclidean and fractal media, ii) re-considered the flip-flop kinetics assuming that the absorption rate for a one-compartment model is governed by an instantaneous rate coefficient instead of a rate constant, and, iii) re-considered the extent of drug absorption as a function of dose using an in vivo reaction limited model of drug dissolution with integer and non-integer stoichiometry values. We found that drug diffusional processes and reactions are slowed down in heterogeneous media and the environmental heterogeneity leads to increased fluctuations of the measurable quantities. Highly variable experimental literature data with measurements in intrathecal space and gastrointestinal fluids were explained accordingly. Next, by applying power law and Weibull input functions to a one-compartment model of disposition we show that the shape of concentration-time curves is highly dependent on the time exponent of the input functions. Realistic examples based on PK data of three compounds known to exhibit flip-flop kinetics are analyzed. The need to use time dependent coefficients instead of rate constants in PBPK modeling and virtual bioequivalence is underlined. Finally, the shape of the fraction absorbed as a function of dose plots, using an in vivo reaction limited model of drug dissolution were found to be dependent on the stoichiometry value and the solubility of drug. Ascending and descending limbs were observed for the higher stoichiometries (2.0 and 1.5) with the low solubility drug. In contrast, for the more soluble drug, a continuous increase of fraction absorbed as a function of dose is observed when the higher stoichiometries are used (2.0 and 1.5). For both drugs, the fraction absorbed for the lower values of stoichiometry (0.7 and 1.0) exhibit a non-dependency on dose profile. Our results give an insight into the complex picture of in vivo drug dissolution since diffusion-limited and reaction-limited processes seem to operate under in vivo conditions concurrently.
MeSH term(s)	Administration, Oral ; Computer Simulation ; Gastrointestinal Absorption/drug effects ; Gastrointestinal Absorption/physiology ; Monte Carlo Method ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/metabolism ; Pharmacokinetics
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2019-01-25
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2019.01.027
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Article ; Online: Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

Acevedo, Alison / Mavroudis, Panteleimon D / DuBois, Debra / Almon, Richard R / Jusko, William J / Androulakis, Ioannis P

Journal of pharmacokinetics and pharmacodynamics

2021 Volume 48, Issue 3, Page(s) 361–374

Abstract: A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways ... ...

Abstract	A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle). A genome-wide pathway-centric analysis enables us to develop a comprehensive picture on how the observed circadian variation at the individual gene level, orchestrates functional responses at the pathway level. Such pathway-based "meta-data" analysis enables the rational integration and comparison across platforms and/or experimental designs evaluating emergent dynamics, as opposed to comparisons of individual elements. One of our key findings is that when considering the dynamics at the pathway level, a complex behavior emerges. Our work proposes that tissues tend to coordinate gene's circadian expression in a way that optimizes tissue-specific pathway activity, depending of each tissue's broader role in homeostasis.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Circadian Rhythm/genetics ; Genomics/methods ; Homeostasis/genetics ; Liver/metabolism ; Lung/metabolism ; Metabolic Networks and Pathways/genetics ; Mice ; Models, Animal ; Muscles/metabolism ; Rats ; Transcriptome
Language	English
Publishing date	2021-03-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-021-09750-3
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Article ; Online: Current Approaches for Predicting Human PK for Small Molecule Development Candidates: Findings from the IQ Human PK Prediction Working Group Survey.

The AAPS journal

2022 Volume 24, Issue 5, Page(s) 85

Abstract: Accurate prediction of human clearance (CL) and volume of distribution at steady state ( ... ...

Abstract	Accurate prediction of human clearance (CL) and volume of distribution at steady state (V
MeSH term(s)	Drug Industry ; Humans ; Kinetics ; Models, Biological ; Pharmaceutical Preparations
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2022-07-19
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-022-00735-9
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Article ; Online: Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits.

Mavroudis, Panteleimon D / Hermes, Helen E / Teutonico, Donato / Preuss, Thomas G / Schneckener, Sebastian

PloS one

2018 Volume 13, Issue 3, Page(s) e0194294

Abstract: The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all ... ...

Abstract	The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations.
MeSH term(s)	Algorithms ; Animals ; Area Under Curve ; Computer Simulation ; Inulin/pharmacokinetics ; Inulin/toxicity ; Models, Biological ; Pharmacokinetics ; Rabbits ; Reproducibility of Results ; Toxicokinetics ; Workflow
Chemical Substances	Inulin (9005-80-5)
Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0194294
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Article ; Online: Daily variation of gene expression in diverse rat tissues.

Mavroudis, Panteleimon D / DuBois, Debra C / Almon, Richard R / Jusko, William J

PloS one

2018 Volume 13, Issue 5, Page(s) e0197258

Abstract: Circadian information is maintained in mammalian tissues by a cell-autonomous network of transcriptional feedback loops that have evolved to optimally regulate tissue-specific functions. An analysis of daily gene expression in different tissues, as well ... ...

Abstract	Circadian information is maintained in mammalian tissues by a cell-autonomous network of transcriptional feedback loops that have evolved to optimally regulate tissue-specific functions. An analysis of daily gene expression in different tissues, as well as an evaluation of inter-tissue circadian variability, is crucial for a systems-level understanding of this transcriptional circuitry. Affymetrix gene chip measurements of liver, muscle, adipose, and lung tissues were obtained from a rich time series light/dark experiment, involving 54 normal rats sacrificed at 18 time points within the 24-hr cycle. Our analysis revealed a high degree of circadian regulation with a variable distribution of phases among the four tissues. Interestingly, only a small number of common genes maintain circadian activity in all tissues, with many of them consisting of "core-clock" components with synchronous rhythms. Our results suggest that inter-tissue circadian variability is a critical component of homeostatic body function and is mediated by diverse signaling pathways that ultimately lead to highly tissue-specific transcription regulation.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Circadian Rhythm/physiology ; Gene Expression/physiology ; Liver/metabolism ; Lung/metabolism ; Male ; Microarray Analysis ; Muscle, Skeletal/metabolism ; Rats, Wistar ; Transcriptome/physiology
Language	English
Publishing date	2018-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0197258
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