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13th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology, Salt Lake City, USA, September 22-26, 2013

13th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology, Salt Lake City, USA, September 22-26, 2013

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  • My name is Jiří Douša and the subject of my presentation is “object oriented PKPD modeling”.
  • I always use the Lego toy system as a metaphor for explaining object orientation to end-users.
  • With Lego objects we build a lego model.
  • And with PKPD objects we can build a PKPD model.We discriminate between the following mainobject categories:Compartment : Container object holding material (e.g. drug).Input : Object that delivers material to a connected target compartment.Output : Object that removes material from a connected source compartment.Transfer : Object that transfers material from a source to a target compartment.Effect : Object that describes the effect in a connected compartment.Tool : General purpose object for additional generic calculations (e.g. Auc, Cav).Patient : Patient object with build-in euations for Bsa, Lbm andCLcr.
  • Examples:TCompartment : Central compartmentTPeripheral : Peripheral compartmentTTransport : One-way transferTDistribution : Two-way transferTInjection : Intravascular bolus inputTInfusion : Intravascular infusionTAbsorption : Extravascular input (e.g. oral, intramuscular)TElimination : First order elimination processTTransformation : Non-linear enzymatic elimination process (MichaelisMenten)TSigmoid : Direct response model (Emax model)TResponse : Indirect response modelPK-Interactions : TInhibition / TCompetitionPD-Interactions : TAntagonism / TSynergismObjects used in the case studies of this presentation:TPortal : Pass-trough compartment with a build-in event controlled output.XInsulin / XGlucose : Specialized insulin / glucose compartments (the “minimal model”).
  • Click through all processes.The key object in this model is the TPortal element. This is a compartment object with build-in inward (accumulation) and outward (excretion) transfers.The outward transfer is event controlled which means that it can be switched on or off using a time table (visible on the right).In this example the outward gate is opened at 4 and 10 hours for a duration of 2 hours. These time points represent meal times that trigger bile excretion into the gut.The MPAG entering the gut this way is hydrolized to MPA, which is reabsorbed again.This process is called enterohepatic circulation.
  • Theenterohepatic circulation phenomenon can be observed as re-absorption peaks in the MPA plasma profile.
  • The key components in this tolbutamide PKPD model are the Insulin and Glucose compartments:These object contain the so called “”minimal models” for Insulin ..... and Glucose.3) Insuline stimulates cellular glucose uptake (utilization) thereby lowering glucose plasma levels.4) Tolbutamide is an oral anti-diabetic drug that improves the insuline release by 2 mechanisms (see sheet).The following interventions can be performed:5) Oral Glucose solution challenges (75 grams)6) Subcutaneous Insulin injections (not used in this example)7) Oral administration of tolbutamide (1 gram)
  • In this example we see the effect of a glucose challenge in a patient via diabetes type 2.There is a poor insulin response in this diabetes patient as demonstrated by the first glucose challenge.A single dose of 1 gram tolbutamide is administered.As a result, the insulin response is improved and is correlated with the tolbutamide plasma concentration.
  • The concept of object oriented PKPD modeling was implemented in two software packages.Edsim++ : A program to visually design PKPD models (you already saw some screen shots in the previous slides)MwPharm++ : A program for Therapeutic Drug Monitoring (the successor of MwPharm).PKPD models created with Edsim++ are stored as XML files which can be employed by MwPharm++ for TDM purposes.
  • The following table lists some characteristics of both software packages.

Salt Lake City 2013 - Presentation Salt Lake City 2013 - Presentation Presentation Transcript

  • Object Oriented PKPD Modeling 13th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology Salt Lake City, USA, September 22-26, 2013 Ing. Jiří Douša, 3rd Medical Faculty Charles University, Prague, Czech Republic Funded by the EU
  • CONTENTS • Object Orientation – Lego Metaphor – PKPD Objects • PKPD Object Library • Case Studies – Mycophenolic Acid (PK model) – Tolbutamide (PKPD model) • Software Implementation – Edsim++ – MwPharm++ • Conclusions
  • OBJECT ORIENTATION Window Object Door Object Roof Objects Brick Objects Desktop Lego Metaphor
  • OBJECT ORIENTATION Lego Model
  • OBJECT ORIENTATION Compartment Input Output Transfer Effect Tool Patient PKPD Objects
  • PKPD OBJECT LIBRARY° Compartment Transfer Input Output Effect TCompartment TTransport TInjection TElimination TSigmoid TPeripheral TDistribution TInfusion TTransformation TResponse TSink TEnzymatic TAbsorption TVirtualElim TKillStatic TPortal TTransit TWeibull THemoDialysis TKillAdaptive TVirtual TLink TGamma TPeriDialysis TKillMic TVirtualLinked TExcretion TAntagonism* XInsulin TMetabolism TSynergism* XGlucose TInhibition* TCompetition* *Interaction objects °Tools not listed. Interactions PK PD
  • CASE STUDY: MYCOPHENOLIC ACID MPAG Renal Elimination (70%) MPA Metabolic Elimination (100%) MPA Renal Elimination (0%) MPA Absorption MPA Distribution MPAG Bile Accumulation (30%) MPAG Bile Excretion
  • CASE STUDY: MYCOPHENOLIC ACID Food intake Enterohepatic Circulation
  • CASE STUDY: TOLBUTAMIDE Insulin Minimal Model Glucose Minimal Model 1) Stimulates insulin release 2) Increases glucose sensitivity ß-cells 1) Stimulates cellular glucose uptake 2) Simulates glycogen synthesis Oral Glucose Challenge (75 g) Oral Tolbutamide (1 g) Subcutaneous Insulin (0 IE)
  • CASE STUDY: TOLBUTAMIDE Glucose Challenge (75 g) Tolbutamide (1 g) Insulin Response
  • SOFTWARE IMPLEMENTATION EDSIM++ Model Designer MWPHARM++ Model User MODEL XML TDMPKPD
  • APPLICATION COOPERATION Edsim++ MwPharm++° Mission Environment Workflow Subject ° Ranked number 1 in a review by Fuchs et al. (Clin Pharmacokinet (2013) 52:9–22) PKPD Modeling • Simulation • Population analysis TDM Process • Dose Calculation • Patient analysis Education, Research Hospital, Clinic Creative, Exploratory Routine, Standards Population Individual
  • CONCLUSIONS • Object oriented PKPD modeling (OOPKPD) is an innovative method applicable to a broad range of modeling problems. • OOPKPD is implemented in the user-friendly software package Edsim++, which can be used in research and education. • The Edsim++ OOPKPD modeling engine can be used by other applications using a software development kit (SDK). • Edsim++ can share PKPD models with MwPharm++, enabling the use of advanced PKPD models in routine TDM. • MwPharm was ranked as the number one TDM software package in a review by Fuchs et al. (2013).
  • Thank you for your attention. Any Questions?
  • CONTACT www.mediware.cz george.dousa@mediware.cz jiri.potucek@mediware.cz