Visual PKPD Modeling

Transcription

1 Visual PKPD Modeling

2 FEATURES Graphical model editor for creation and modification of compartment models. Immediate simulation of the created model and display of the result. Large extendable library of PKPD modeling objects. Display results graphically in compartments and charts, and numerically in tables. Charts and tables can be directly exported in Microsoft Excel format. Repetitive superimposable event schedules (e.g. dosing or hemodialysis) Modeling of complex PK, PD and PKPD-interactions. Allometric scaling of any model parameter to different patient variables. Fitting of model parameters to a given data set. Monte Carlo simulation of selected model parameters. Generic dose calculation on selected output variable (e.g. concentration or effect). Suitable for research and education. Programming of new PKPD objects and application plug-ins in C#. Exchange of models with MwPharm++ and data with Microsoft Office and OpenOffice. Runs under Microsoft Windows XP, Vista, 7 and 8. RESEARCH AND EDUCATION Edsim++ is an object oriented visual pharmacokinetic pharmacodynamics (PKPD) modeling tool. Its elegant and innovative user interface makes the software extremely simple to use so that it is well suited for teaching pharmacokinetics. Edsim++ is equipped with a large number of advanced PKPD objects that can be used for building complex models as required in a research environment. OBJECT ORIENTED MODELING Edsim++ employs the concept of object oriented modeling (OOM). PKPD processes are represented by objects that can be dragged upon the desktop, after which the objects can be connected to each other. Double clicking an object expands the object properties window giving access to the details of the object (constants, parameters, variables, observations, events, etc). Objects are categorized into compartments, inputs, outputs, transfers, effects, and tools (see PKPD object library). SIMULATION AND FITTING All object parameters have default parameters so that a constructed model can be simulated directly without having to enter numerous parameter values first. Model parameters can be fitted to variable observations. Alternatively, model parameters can be randomized in Monte Carlo Simulations. DATA EXCHANGE Model diagrams can be exported as Microsoft Visio diagrams (VDX). Simulation output data can be saved as Microsoft Excel workbooks (XLS). Models can be reused with the new MwPharm++ application for use in therapeutic drug monitoring (TDM).

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4 CASE STUDY: ENTEROHEPATIC CIRCULATION OF MPA Mycophenolic acid (MPA) is an immunosuppressant drug used to prevent rejection in organ transplantation. MPA is administered orally (typically 500 mg per 12 hours). The prodrug MMF (mycophenolate mofetil ester) is also given because of improved bioavailability. MMF is rapidly hydrolized to MPA by esterases (plasma, liver, and kidney). MPA shows 2-compartment kinetics. Only a minor fraction of MPA is eliminated renally. The major route of elimination is conjugation (mainly in the liver) to the glucoronide MPAG. A large fraction of MPAG is eliminated renally. A small but significant fraction is excreted into the bile. Emptying of the gall bladder into the gut is triggered by food intake. If this happens, MPAG is hydrolized to MPA, after which it is reabsorbed again from the gut. These events may show up as small secondary peaks in the MPA plasma profile. This phenomenon is called enterohepatic circulation (also known as enterohepatic cycle) Variable MPA2.C (mg/l) MPAG4.C (mg/l) Time (h) 2-compartment MPA kinetics was modeled using a TCompartment object (MPA2) and a TPeripheral object (MPA3). First-order absorption is represented by a TAbsorption object (MPA1). Renal elimination of MPA and MPAG was modeled by two TElimination objects (MPA0 and MPAG0). Conjugation of MPA to MPAG was modeled using a TSink object (MPAG4). The key object in this model is the TPortal object (MPAG5) representing the gall bladder. A TPortal object accumulates drug from the connected source compartment just like a TSink object does (first-order transfer). In addition, a TPortal object can also deliver drug to a connected target object (also first-order transfer). What makes a TPortal object special is that this drug delivery can be switched on and off using an event schedule. In this example we simulated gall bladder emptying by adding two events to the MPAG5 object representing meal intake at 4 and 10 hours.

5 PKPD OBJECT LIBRARY Category Type Description Compartment TCompartment Central compartment with amount, volume and concentration. TSink Compartment with build-in 1-way first-order transport (sink). TPeripheral Compartment with build-in 2-way first-order transport (distribution). TPortal Sink compartment with build-in event-controlled first-order output. TVirtual Compartment with an infinitely small volume of distribution. TVirtualLinked Virtual compartment with build-in 1-way first-order transport (no mass transfer) XGlucose Specialized compartment implementing the glucose minimal model. XInsuline Specialized compartment implementing the insulin minimal model. XInsulineEx XInsulin subtype whose effect is modulated by an anti-diabetic drug. Input TInjection Intravenous injection input (bolus). TInfusion Intravenous zero order infusion input. TAbsorption Extravascular first-order infusion input. TGamma Gamma distribution function input. TWeibull Weibull distribution function input. Output TElimination First-order linear elimination output. TTransformation Non-linear elimination output (Michaelis-Menten kinetics). TVirtualElimination First-order linear elimination output used with virtual compartments. THemoDialysis Artificial flow based elimination output (hemodialysis). TPeriDialysis Artificial batch based elimination output (peritoneal dialysis). Transfer TTransport First-order linear transfer (1-way). TEnzymatic Non-linear elimination transfer (Michaelis-Menten kinetics). TDistribution Two-way linear first-order transfer (2-way distribution). TMetabolism Metabolite specification of an elimination output object. TExcretion Excretion specification of an elimination output object. TTransit Composite transfer object with build-in multiple transit compartments. TGate TTransport subtype with event controlled output. TLink First-order linear transfer. TCompetition PK interaction object (competitive, non-competitive and uncompetitive). Effect TSigmoid Classic sigmoidal Emax direct effect model (including Hill coefficient). TResponse Indirect effect model (Jusko model) TAntagonism PD competitive interaction object (Emax interaction model). TSynergism PD synergy interaction object (Greco interaction model). TKillStatic Static bacterial killing model. TKillAdaptive Adaptive bacterial killing model. TKillMic MIC based bacterial killing model (Meagher model). Tool TAddition Adds two variables from two different objects. TSubtraction Subtracts two variables from two different objects. TMultiplier Applies a multiplier to any object variable. TIntegrator Integrates any object variable (area and average). TLevel Time above level monitoring tool (e.g. time above MIC). TMonitor Tool for exposing any model symbol as a chartable variable. TReference Tool for displaying variable reference lines (e.g. min, max, tox, mic). TPolyExp Poly-exponential model implementation used in validation (base objects). TPolyExp2 Poly-exponential model implementation used in validation (derived objects). Patient TPatient Patient object taking as input age, weight, height and creatinine levels. Calculates body mass index, body surface area and creatinine clearance. Incorporates a complete creatinine turnover model that takes into account interventions like hemodialysis. The patient object is typically used for the allometric scaling of model parameters.

6 CONTACT INFORMATION Address: MEDIWARE a.s. Evropská 655/ Praha 6 Czech Republic Chairman of the Board of Directions: Ing. Jiří Potůček, CSc. Tel: jiri.potucek@mediware.cz Technical support: Ing. Jirí Douša Tel: george.dousa@mediware.cz Internet: