Dataset Information

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

ABSTRACT: Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration-time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development.

SUBMITTER: Yamamoto Y

PROVIDER: S-EPMC5702903 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Yamamoto Yumi Y Välitalo Pyry A PA Huntjens Dymphy R DR Proost Johannes H JH Vermeulen An A Krauwinkel Walter W Beukers Margot W MW van den Berg Dirk-Jan DJ Hartman Robin R Wong Yin Cheong YC Danhof Meindert M van Hasselt John G C JGC de Lange Elizabeth C M ECM

CPT: pharmacometrics & systems pharmacology 20171013 11

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs ...[more]

PMID: 28891201

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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

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Publications

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

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