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
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
° Ranked number 1 in a review by Fuchs et al. (Clin Pharmacokinet (2013) 52:9–22)
• Population analysis
• Dose Calculation
• Patient analysis
Education, Research Hospital, Clinic
Creative, Exploratory Routine, Standards
• 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).