Applied Concepts in PBPK Modeling: How to Build a PBPK/PD Model

The aim of this tutorial is to introduce the fundamental concepts of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on their practical implementation in a typical PBPK model building workflow. To illustrate basic steps in PBPK model building, a PBPK model for ciprofloxacin will be constructed and coupled to a pharmacodynamic model to simulate the antibacterial activity of ciprofloxacin treatment.

[1]  A. Baumann Early development of therapeutic biologics--pharmacokinetics. , 2006, Current drug metabolism.

[2]  M Rowland,et al.  Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations Principles, Methods, and Applications in the Pharmaceutical Industry , 2013, CPT: pharmacometrics & systems pharmacology.

[3]  N Parrott,et al.  Physiologically based pharmacokinetic modeling in drug discovery and development: A pharmaceutical industry perspective , 2015, Clinical pharmacology and therapeutics.

[4]  P. Artursson,et al.  Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. , 1991, Biochemical and biophysical research communications.

[5]  H Lennernäs,et al.  Intestinal permeability and its relevance for absorption and elimination , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[6]  Kiyohiko Sugano,et al.  Prediction of human intestinal permeability using artificial membrane permeability. , 2003, International journal of pharmaceutics.

[7]  Jingjing Yu,et al.  Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification , 2015, Drug Metabolism and Disposition.

[8]  Michael Gertz,et al.  Hepatocellular Binding of Drugs: Correction for Unbound Fraction in Hepatocyte Incubations Using Microsomal Binding or Drug Lipophilicity Data , 2008, Drug Metabolism and Disposition.

[9]  Jason H T Bates,et al.  Multi-scale lung modeling. , 2011, Journal of applied physiology.

[10]  Yuichi Sugiyama,et al.  In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. , 2009, Drug metabolism and pharmacokinetics.

[11]  T R Pieber,et al.  A Generic Integrated Physiologically based Whole-body Model of the Glucose-Insulin-Glucagon Regulatory System , 2013, CPT: pharmacometrics & systems pharmacology.

[12]  T. Lavé,et al.  A Novel Strategy for Physiologically Based Predictions of Human Pharmacokinetics , 2006, Clinical pharmacokinetics.

[13]  B Agoram,et al.  Predicting the impact of physiological and biochemical processes on oral drug bioavailability. , 2001, Advanced drug delivery reviews.

[14]  S. Thomas Kidney modeling and systems physiology. , 2009 .

[15]  R. Hansen,et al.  Antibody pharmacokinetics and pharmacodynamics. , 2004, Journal of pharmaceutical sciences.

[16]  L. Blank,et al.  Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients , 2016, Archives of Toxicology.

[17]  R K Jain,et al.  Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. , 1994, Cancer research.

[18]  E. Schuck,et al.  Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of a Once-Daily Treatment Using Ciprofloxacin in an Extended-Release Dosage Form* , 2005, Infection.

[19]  M. Rowland,et al.  Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. , 2005, Journal of pharmaceutical sciences.

[20]  J. Dressman,et al.  Cytochrome P450‐mediated metabolism in the human gut wall , 2009 .

[21]  J. Manson,et al.  The Pharmacokinetics of The Biliary Excretion of Ciprofloxacin , 1989, HPB surgery : a world journal of hepatic, pancreatic and biliary surgery.

[22]  M. Rowland,et al.  Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. , 2006, Journal of pharmaceutical sciences.

[24]  L. Salphati,et al.  Evaluation of a single‐pass intestinal‐perfusion method in rat for the prediction of absorption in man , 2001, The Journal of pharmacy and pharmacology.

[25]  F. Theil,et al.  Prediction of adipose tissue: plasma partition coefficients for structurally unrelated drugs. , 2001, Journal of pharmaceutical sciences.

[26]  Dhaval K. Shah,et al.  Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human , 2011, Journal of Pharmacokinetics and Pharmacodynamics.

[27]  P Vicini,et al.  A Mechanistic, Multiscale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 2—Model Applications , 2014, CPT: pharmacometrics & systems pharmacology.

[28]  F. Zijlstra,et al.  Diabetes insipidus associated with dysplastic pancytopenia. , 1987, American Journal of Medicine.

[29]  Meindert Danhof,et al.  Systems pharmacology - Towards the modeling of network interactions. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[30]  S-M Huang,et al.  Regulatory Experience With Physiologically Based Pharmacokinetic Modeling for Pediatric Drug Trials , 2012, Clinical pharmacology and therapeutics.

[31]  Ryosei Kawai,et al.  Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125 , 1994, Journal of Pharmacokinetics and Biopharmaceutics.

[32]  Ernesto Callegari,et al.  Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding , 2005, Journal of Pharmacology and Experimental Therapeutics.

[33]  Walter Schmitt,et al.  General approach for the calculation of tissue to plasma partition coefficients. , 2008, Toxicology in vitro : an international journal published in association with BIBRA.

[34]  Jan Snoeys,et al.  From preclinical to human – prediction of oral absorption and drug–drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach in an industrial setting: a workflow by using case example , 2012, Biopharmaceutics & drug disposition.

[35]  L. Kuepfer,et al.  Development of a Physiologically Based Computational Kidney Model to Describe the Renal Excretion of Hydrophilic Agents in Rats , 2013, Front. Physio..

[36]  Rolf Burghaus,et al.  Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban—an oral, direct Factor Xa inhibitor , 2014, Front. Physiol..

[37]  J. Hampe,et al.  A Mechanistic, Model-Based Approach to Safety Assessment in Clinical Development , 2012, CPT: pharmacometrics & systems pharmacology.

[38]  G. Drusano An overview of the pharmacology of intravenously administered ciprofloxacin. , 1987, The American journal of medicine.

[39]  J. Dressman,et al.  Cytochrome P450-mediated metabolism in the human gut wall. , 2009, The Journal of pharmacy and pharmacology.

[40]  Wolfgang Weiss,et al.  A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks , 2011, Front. Physio..

[41]  N. Stockbridge,et al.  A proposal for scientific framework enabling specific population drug dosing recommendations , 2015, Journal of clinical pharmacology.

[42]  M. Block Physiologically based pharmacokinetic and pharmacodynamic modeling in cancer drug development: status, potential and gaps , 2015, Expert opinion on drug metabolism & toxicology.

[43]  Stefan Willmann,et al.  Using Bayesian-PBPK modeling for assessment of inter-individual variability and subgroup stratification , 2013, In Silico Pharmacology.

[44]  Paolo Magni,et al.  Predictive Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Kinetics in Xenograft Models after Administration of Anticancer Agents , 2004, Cancer Research.

[45]  Tobias Preußer,et al.  Spatio-Temporal Simulation of First Pass Drug Perfusion in the Liver , 2014, PLoS Comput. Biol..

[46]  J. Dressman,et al.  Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions. , 2011, Journal of pharmaceutical sciences.

[47]  Hannah M. Jones,et al.  Modelling and PBPK Simulation in Drug Discovery , 2009, The AAPS Journal.

[48]  M. Monshouwer,et al.  Fluoroquinolone antibiotics inhibit cytochrome P450-mediated microsomal drug metabolism in rat and human. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[49]  A. Smith,et al.  Pharmacokinetics of ciprofloxacin in cystic fibrosis , 1987, Antimicrobial Agents and Chemotherapy.

[50]  M Rowland,et al.  Best Practice in the Use of Physiologically Based Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory Questions , 2012, Clinical pharmacology and therapeutics.

[51]  Jeffrey R. Chabot,et al.  Comprehensive mechanism-based antibody pharmacokinetic modeling , 2011, 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[52]  Stefan Willmann,et al.  Physiology-Based Simulations of a Pathological Condition , 2008, Clinical pharmacokinetics.

[53]  S. Batra,et al.  A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs. , 2008, International immunopharmacology.

[54]  R K Jain,et al.  Biodistribution of monoclonal antibodies: scale-up from mouse to human using a physiologically based pharmacokinetic model. , 1995, Cancer research.

[55]  Stefan Willmann,et al.  Mechanism-based prediction of particle size-dependent dissolution and absorption: cilostazol pharmacokinetics in dogs. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[56]  W. Nimmo,et al.  Novel drug delivery and its therapeutic application , 1989 .

[57]  B. Haraldsson,et al.  Fluid and protein fluxes across small and large pores in the microvasculature. Application of two-pore equations. , 1987, Acta physiologica Scandinavica.

[58]  Jörg Lippert,et al.  From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools , 2005, Expert opinion on drug metabolism & toxicology.

[59]  P. Costa,et al.  Modeling and comparison of dissolution profiles. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[60]  K Rowland-Yeo,et al.  Basic Concepts in Physiologically Based Pharmacokinetic Modeling in Drug Discovery and Development , 2013, CPT: pharmacometrics & systems pharmacology.

[61]  F. Theil,et al.  A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. , 2000, Journal of pharmaceutical sciences.

[62]  L. Kuepfer,et al.  Using Expression Data for Quantification of Active Processes in Physiologically Based Pharmacokinetic Modeling , 2012, Drug Metabolism and Disposition.

[63]  P. H. van der Graaf,et al.  Integrated Pharmacometrics and Systems Pharmacology Model-Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis , 2012, CPT: pharmacometrics & systems pharmacology.

[64]  T. Bergan,et al.  Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses , 1986, European Journal of Clinical Microbiology.

[65]  J. Tolan,et al.  MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening. , 1999, Journal of pharmaceutical sciences.

[66]  A Rostami-Hodjegan,et al.  Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro-in vivo extrapolation of oral drug absorption. , 2013, Biopharmaceutics & drug disposition.

[67]  M. Jamei,et al.  Are Physiologically Based Pharmacokinetic Models Reporting the Right Cmax? Central Venous Versus Peripheral Sampling Site , 2015, The AAPS Journal.

[68]  G. Tucker,et al.  Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors , 2004, Xenobiotica; the fate of foreign compounds in biological systems.

[69]  Jörg Keldenich,et al.  Multilamellar Liposomes and Solid-Supported Lipid Membranes (TRANSIL): Screening of Lipid-Water Partitioning Toward a High-Throughput Scale , 2001, Pharmaceutical Research.

[70]  W Wang,et al.  Monoclonal Antibody Pharmacokinetics and Pharmacodynamics , 2008, Clinical pharmacology and therapeutics.

[71]  Walter Schmitt,et al.  PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model , 2003 .

[72]  Steven W. Martin,et al.  The role of mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modelling in translational research of biologics. , 2007, Drug discovery today.

[73]  Christos Reppas,et al.  Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms , 2004, Pharmaceutical Research.

[74]  Joseph P. Balthasar,et al.  Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice , 2007, Journal of Pharmacokinetics and Pharmacodynamics.

[75]  L. Berezhkovskiy,et al.  Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination. , 2004, Journal of pharmaceutical sciences.

[76]  Shiew-Mei Huang,et al.  Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of an FDA Public Workshop on PBPK , 2015, CPT: pharmacometrics & systems pharmacology.

[77]  Stefan Willmann,et al.  Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part II: extension to describe performance of solid dosage forms. , 2012, Journal of pharmaceutical sciences.

[78]  G. Grass,et al.  In Vitro Measurement of Gastrointestinal Tissue Permeability Using a New Diffusion Cell , 1988, Pharmaceutical Research.

[79]  Amin Rostami-Hodjegan,et al.  Simulation and prediction of in vivo drug metabolism in human populations from in vitro data , 2007, Nature Reviews Drug Discovery.

[80]  Anna M. Wu,et al.  A Predictive Model of Therapeutic Monoclonal Antibody Dynamics and Regulation by the Neonatal Fc Receptor (FcRn) , 2005, Annals of Biomedical Engineering.

[81]  Sheila Annie Peters,et al.  Comprar Physiologically Based Pharmacokinetic (PBPK) Modeling And Simulations. Principles, Methods, And Applications In The Pharmaceutical Industry | Sheila Annie Peters | 9780470484067 | Wiley , 2012 .

[82]  D. Levitt PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics , 2002, BMC clinical pharmacology.

[83]  W. Huisinga,et al.  Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models , 2014, Journal of Pharmacokinetics and Pharmacodynamics.

[84]  L. Aarons,et al.  Quantitative Structure-Pharmacokinetics Relationships: I. Development of a Whole-Body Physiologically Based Model to Characterize Changes in Pharmacokinetics Across a Homologous Series of Barbiturates in the Rat , 1997, Journal of Pharmacokinetics and Biopharmaceutics.

[85]  A. Edginton,et al.  Physiologically Based Pharmacokinetic Modeling and Simulation in Pediatric Drug Development , 2014, CPT: pharmacometrics & systems pharmacology.

[86]  Evaluation of a Catenary PBPK Model for Predicting the In Vivo Disposition of mAbs Engineered for High-Affinity Binding to FcRn , 2012, The AAPS Journal.

[87]  J. DiStefano,et al.  A two-tiered physiologically based model for dually labeled single-chain Fv-Fc antibody fragments , 2006, Molecular Cancer Therapeutics.

[88]  Walter Schmitt,et al.  A physiological model for the estimation of the fraction dose absorbed in humans. , 2004, Journal of medicinal chemistry.

[89]  W. R. Lieb,et al.  Biological Membranes behave as Non-porous Polymeric Sheets with Respect to the Diffusion of Non-electrolytes , 1969, Nature.

[90]  J. Cardot,et al.  In Vitro–In Vivo Correlation: Importance of Dissolution in IVIVC , 2007 .

[91]  J. Stelling,et al.  Ensemble modeling for analysis of cell signaling dynamics , 2007, Nature Biotechnology.

[92]  G R Wilkinson,et al.  Clearance approaches in pharmacology. , 1987, Pharmacological reviews.

[93]  U. Hofmann,et al.  A systematic evaluation of the use of physiologically based pharmacokinetic modeling for cross-species extrapolation. , 2015, Journal of pharmaceutical sciences.

[94]  T. Baillie,et al.  Extrapolation of Diclofenac Clearance from in Vitro Microsomal Metabolism Data: Role of Acyl Glucuronidation and Sequential Oxidative Metabolism of the Acyl Glucuronide , 2002, Journal of Pharmacology and Experimental Therapeutics.

[95]  Matthias Hermes,et al.  Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration , 2010, Proceedings of the National Academy of Sciences.

[96]  B. Haraldsson,et al.  Transport of macromolecules across microvascular walls: the two-pore theory. , 1994, Physiological reviews.

[97]  M. Jamei,et al.  A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: A tale of 'bottom-up' vs 'top-down' recognition of covariates. , 2009, Drug metabolism and pharmacokinetics.

[98]  D. Levitt Physiologically based pharmacokinetic modeling of arterial – antecubital vein concentration difference , 2004, BMC clinical pharmacology.

[99]  A Nordmark,et al.  Physiologically Based Models in Regulatory Submissions: Output From the ABPI/MHRA Forum on Physiologically Based Modeling and Simulation , 2015, CPT: pharmacometrics & systems pharmacology.

[100]  P Vicini,et al.  A Mechanistic, Multiscale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 1—Theoretical Model , 2014, CPT: pharmacometrics & systems pharmacology.

[101]  Steffen Borchers,et al.  Integrating Cellular Metabolism into a Multiscale Whole-Body Model , 2012, PLoS Comput. Biol..

[102]  H. Landahl,et al.  Relationship of Octanol/Water Partition Coefficient and Molecular Weight to Cellular Permeability and Partitioning in S49 Lymphoma Cells , 1984, Pharmaceutical Research.

[103]  J S Barrett,et al.  Application of Physiologically Based Pharmacokinetic Modeling to Predict Acetaminophen Metabolism and Pharmacokinetics in Children , 2013, CPT: pharmacometrics & systems pharmacology.