Dataset Information

Physiologically Based Pharmacokinetic Modelling and Simulation to Predict the Plasma Concentration Profile of Doxorubicin.

ABSTRACT: Doxorubicin (DOX) is still an important anticancer agent despite its tricky pharmacokinetics (PK) and toxicity potential. The advent of systems pharmacology enables the construction of PK models able to predict the concentration profiles of drugs and shed light on the underlying mechanisms involved in PK and pharmacodynamics (PD). By utilizing existing published data and by analysing two clinical case studies we attempt to create physiologically based pharmacokinetic (PBPK) models for DOX using widely accepted methodologies. Based on two different approaches on three different key points we derived eight plausible models. The validation of the models provides evidence that is all performing as designed and opens the way for further exploitation by integrating metabolites and pharmacogenomic information.

SUBMITTER: Mystridis GA

PROVIDER: S-EPMC8949582 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Physiologically Based Pharmacokinetic Modelling and Simulation to Predict the Plasma Concentration Profile of Doxorubicin.

Mystridis George A GA Batzias Georgios C GC Vizirianakis Ioannis S IS

Pharmaceutics 20220228 3

Doxorubicin (DOX) is still an important anticancer agent despite its tricky pharmacokinetics (PK) and toxicity potential. The advent of systems pharmacology enables the construction of PK models able to predict the concentration profiles of drugs and shed light on the underlying mechanisms involved in PK and pharmacodynamics (PD). By utilizing existing published data and by analysing two clinical case studies we attempt to create physiologically based pharmacokinetic (PBPK) models for DOX using ...[more]

PMID: 35335919

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Project description:BackgroundModeling of pharmacokinetic parameters and pharmacodynamic actions requires knowledge of the arterial blood concentration. In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.MethodsA physiologically based pharmacokinetic (PBPK) model for the tissues drained by the antecubital vein (referred to as "arm") is developed. It is assumed that the "arm" is composed of tissues with identical properties (partition coefficient, blood flow/gm) as the whole body tissues plus a new "tissue" representing skin arteriovenous shunts. The antecubital vein concentration depends on the following parameters: the fraction of "arm" blood flow contributed by muscle, skin, adipose, connective tissue and arteriovenous shunts, and the flow per gram of the arteriovenous shunt. The value of these parameters was investigated using simultaneous experimental measurements of arterial and antecubital concentrations for eight solutes: ethanol, thiopental, 99Tcm-diethylene triamine pentaacetate (DTPA), ketamine, D2O, acetone, methylene chloride and toluene. A new procedure is described that can be used to determine the arterial concentration for an arbitrary solute by deconvolution of the antecubital concentration. These procedures are implemented in PKQuest, a general PBPK program that is freely distributed http://www.pkquest.com.ResultsOne set of "standard arm" parameters provides an adequate description of the arterial/antecubital vein concentration for ethanol, DTPA, thiopental and ketamine. A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state.ConclusionsUsing the set of "standard arm" parameters, the antecubital vein concentration can be used to determine the whole body PBPK model parameters for an arbitrary solute without any additional adjustable parameters. Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

Dataset Information

Physiologically Based Pharmacokinetic Modelling and Simulation to Predict the Plasma Concentration Profile of Doxorubicin.

Publications

Physiologically Based Pharmacokinetic Modelling and Simulation to Predict the Plasma Concentration Profile of Doxorubicin.

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