Create Pharmacokinetic Models
Ways to Create or Import Pharmacokinetic Model
To start modeling, you can:
Create a PK model using a model construction wizard that lets you specify the number of compartments, the route of administration, and the type of elimination.
Extend any model to build higher fidelity models.
Build or load your own model. Load a SimBiology^{®} project or SBML model.
How SimBiology Models Represent Pharmacokinetic Models
The following figure compares a model as typically represented in pharmacokinetics with the same model shown in the SimBiology model diagram. For this comparison, assume that you are modeling administration of a drug using a twocompartment model with any dosing input and linear elimination kinetics. (The model structure remains the same with any dosing type.)
Note the following:
SimBiology represents the concentration or amount of a drug in a given compartment or volume by a species object contained within the compartment.
SimBiology represents the exchange or flow of the drug between compartments and the elimination of the drug by reactions.
SimBiology represents intercompartmental clearance by a parameter (
Q
) which specifies the clearance between the compartments.SimBiology drives the dosing schedule with a combination of species (
Drug
and/orDose
) and reactions (Dose > Drug
), depending on whether the administration into the compartment follows bolus, zeroorder, infusion, or firstorder dosing kinetics. For more information on the components added and parameters estimated, see Dosing Types.
You can also view this model as a regression function, y
= f(k,u)
, where y
is the predicted value,
given values of an input u
, and parameter values k
.
In SimBiology the model represents f
, and
the model is used to generate a regression function if y
, k
,
and u
are identified in the model.
Dosing Types
When creating models, SimBiology creates the following model components for each compartment in the model, regardless of the dosing type:
Two species (
Drug_CompartmentName
andDose_CompartmentName
) for each compartment.A reaction (
Dose_CompartmentName > Drug_CompartmentName
) for each compartment, governed by mass action kinetics.A parameter (
ka_CompartmentName
) for each compartment, representing the absorption rate of the drug when absorption follows firstorder kinetics. This is the forward rate parameter for theDose_CompartmentName > Drug_CompartmentName
reaction.A parameter (
Tk0_CompartmentName
) for each compartment, representing the duration of drug absorption when absorption follows zeroorder kinetics.A parameter (
TLag_CompartmentName
) for each compartment, representing the time lag for any dose that targets that compartment and also that is specified as having a time lag.
For dosing types that have a fixed infusion or absorption duration
(infusion
and zeroorder
), you
can use overlapping doses. The doses are additive.
The following table describes the dosing types, the default parameters to estimate, and lists the model components created and used for dosing.
Dosing Type  Description  SimBiology Model Components Used  Default Parameters to Estimate 

'' (empty character vector)  No dose  The species (  None 
SimBiology Model Builder app —
Command line —
 Assumes that the drug amount is increased instantly at the dose time. In the SimBiology model, the initial concentration of the drug is based on dose amount and volume of the compartment containing the drug.  The species (  None 
SimBiology Model Builder app —
Command line —
 Assumes that the infused drug amount increases at a constant known absorption (or infusion) rate over a known duration. The imported data set must contain the rate and not an infusion duration. SimBiology uses this information to change the species concentration at the constant rate over the duration specified in the data set.  The species (  None 
SimBiology Model Builder app —
Command line —
 Assumes that the drug is added at a constant rate over fixed, but unknown duration. 


SimBiology Model Builder app —
Command line —
 Assumes that the rate at which the drug is absorbed is not constant. In the SimBiology model, absorption rate is assumed to be governed by massaction kinetics. 


Elimination Types
Elimination Type  Description  SimBiology Model Components Created  Default Parameters to Estimate 

SimBiology Model Builder app — Command line —
 Assumes simple massaction kinetics in the elimination of the
drug. In the SimBiology model, elimination is specified by massaction
kinetics with the elimination rate constant specified by the forward
rate parameter (ke ). 


SimBiology Model Builder app — Command line —
 Assumes simple massaction kinetics in the elimination of the
drug. In the SimBiology model, similar to Linear
{Elimination Rate, Volume} . But, in addition, this option
lets you specify the model in terms of clearance (Cl )
where, Cl = ke * volume ). 


SimBiology Model Builder app — Command line —
 Assumes that elimination is governed by MichaelisMenten kinetics. 


Intercompartmental Clearance
The compartments created when you generate a SimBiology model
form a chain and each pair of linked compartments are connected by
a transport reaction similar to linear elimination. The addition of
two compartments, C1
and C2
,
generates a reversible massaction reaction C1.Drug_C1 <>
C2.Drug
. The forward rate parameter is the compartmental
clearance, Q_{12}
, divided
by the volume of C1
. The reverse rate parameter
is Q_{12}
, divided by the volume
of C2
.
The process of adding each pair of compartments in the chain C_{m}
and C_{n}
generates
the following model components:
A parameter
Q_{mn}
representing the compartmental clearance between those two compartments. This parameter is added to the list of parameters to be estimated (Estimated
property ofPKModelMap
object).A parameter (
kmn
) representing the rate of transfer of the drug fromCm
toCn
, wherek_{mn} = Q_{mn}/V_{m}
.A parameter (
knm
) representing the rate ofCn
toCm
, wherek_{nm} = Q_{mn}/V_{n}
.A reversible massaction reaction between the two compartments,
Cm.Drug_Cm <> Cn.Drug_Cn
, with forward rate parameterkmn
, and reverse rate parameterknm
.An initial assignment rule that initializes the value of the parameter
kmn
, based on the initial values forCm
andQmn
.An initial assignment rule that initializes the value of the parameter
knm
, based on the initial values forCn
andQmn
.
Unit Conversion for Imported Data
Unit conversion converts the matching physical quantities to one consistent unit system in order to resolve them. This conversion is in preparation for correct simulation, but SimBiology returns the physical quantities in the model in units that you specify.
Regardless of whether unit conversion is on
or off
, you
must express dosing data in amount. By default, Unit Conversion is
off
, so you must ensure that units for the data and the model are
consistent with one another. If Unit Conversion is
on
, you must specify units.
Parameters in the model have default units. If unit conversion
is on
, you can change the units as long as the
dimensions are consistent. These default units, which you might use
to specify the values for the initial guess, are as follows.
Physical Quantity or Model Parameter  Unit 

Central or peripheral compartment volume (Central or Peripheral)  liter 
Firstorder elimination rate (ke)  1/second 
Michaelis constant (Km)  milligram/liter 
Maximum reactionvelocity, MichaelisMenten kinetics (Vm)  milligram/second 
Clearance (Cl)  liter/second 
Absorption duration (Tk0)  second 
Absorption rate (ka)  1/second 
Use the configuration settings options to turn unit conversion on
or off
.
For details, see Model Simulation.
For details on dimensional analysis for reaction rates, see How Reaction Rates Are Evaluated.
Create a Pharmacokinetic Model Using the Command Line
To create a PK model with the specified number of compartments, dosing type, and method of elimination:
Create a
PKModelDesign
object. ThePKModelDesign
object lets you specify the number of compartments, route of administration, and method of elimination, which SimBiology uses to construct the model object with the necessary compartments, species, reactions, and rules.pkm = PKModelDesign;
Add a compartment specifying the compartment name, and optionally, the type of dosing, and the method of elimination. Also specify whether the data contains a response variable measured in this compartment and whether the dose(s) have time lags. For example, specify a compartment named
Central
, withBolus
for theDosingType
property,linearclearance
for theEliminationType
property, andtrue
for theHasResponseVariable
property.pkc1 = addCompartment(pkm, 'Central', 'DosingType', 'Bolus', ... 'EliminationType', 'linearclearance', ... 'HasResponseVariable', true);
For a description of other
DosingType
andEliminationType
property values, see Dosing Types and Elimination Types.For a description of the
HasResponseVariable
property, seeHasResponseVariable
. At least one compartment in a model must have a response. Although SimBiology supports multiple responses per compartment, when adding compartments to aPKModelDesign
object, you are limited to one response per compartment.Note
To add a compartment that has a time lag associated with any dose that targets it, set the
HasLag
property totrue
:pkc_lag = addCompartment(pkm, 'Central', 'DosingType', 'Bolus', ... 'EliminationType', 'linearclearance', ... 'HasResponseVariable', true, 'HasLag', true);
Or after adding a compartment, set its
HasLag
property totrue
:pkc1.HasLag = true;
Optionally, add a second compartment named
Peripheral
, with no dosing, no elimination, and no time lag. Set theHasResponseVariable
property totrue
. If you are using the tobramycin data set [1], skip this step and use only one compartment.pkc2 = addCompartment(pkm, 'Peripheral', 'HasResponseVariable', true);
The model construction process adds the necessary parameters, including a parameter representing intercompartmental clearance
Q
. You can add more compartments by repeating this step. The addition of each compartment creates a chain of compartments in the order of compartment addition, with a bidirectional flow of the drug between compartments in the model.Use the handle to the compartment (
pkc1
orpkc2
), to change compartment properties.Construct a SimBiology model object.
[modelObj, PKModelMapObj] = pkm.construct
The
construct
method returns a SimBiology model object (modelObj
) and aPKModelMap
object (PKModelMapObj
) that contains the mapping of the model components to the elements of the regression function.Note
If you change the
PKModelDesign
object, you must create a new model object using theconstruct
method. Changes to thePKModelDesign
do not automatically propagate to a previously constructed model object.Perform parameter fitting using Nonlinear Regression or Nonlinear MixedEffects Modeling.
The model object and the PKModelMap
object are input
arguments for the sbionlmefit
, sbionlmefitsa
and
sbionlinfit
functions used in parameter fitting.
Related Topics
 Calculate NCA Parameters and Fit Model to PK/PD Data Using SimBiology Model Analyzer
 Fit OneCompartment Model to Individual PK Profile
 Fit TwoCompartment Model to PK Profiles of Multiple Individuals
 Estimate CategorySpecific PK Parameters for Multiple Individuals
 Estimate the Bioavailability of a Drug
 Model the Population Pharmacokinetics of Phenobarbital in Neonates