This experiment mainly explains the determination of pkpd using WinNonlin Software widely. WinNonlin software widely used software for the kinetics and dynamic determination. Using CADD subject

1. M. Pharm (Pharmaceutics)
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Rahul Pal*, Prachi Pandey
Department of Pharmaceutics, NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan,
India
Object: To determine the pharmacokinetics and pharmacodynamics of propranolol using WinNonlin®
Software.
References:
01. Certara PhoenixTM
software to Pk/PD management and analysis; https://www.certara
.com/software/pkpd.org
02. Pereira, Laiz Compos et. Al, “Pharmacokinetic/Pharmacodynamic modeling and app. In
antibacterial/fungal pharmacotherapy: A Narrative review”, Antibiotics, Vol. 11, (8); pages no.:
986, 22 July 2022, doi: 10.3390/antibiotics11080986.
Requirements:
• Chemical Moiety: Propranolol
• Software: Phoenix TM
, WinNonlin (subscription) & trial version also used.
Theory:
WinNonlin software are calculates the pk/pd of drug. Propranolol is beta-blocker uses to treat
hypertension, angina & arrhythmias. To calculate its Pk/Pd through WinNonlin software.
The basics steps of software to determine the PK/PD value with WinNonlin software as following:
− Import the data into the WinNonlin software.
− Select the appropriate PK/PD Model
− Fit the model to your data
− Evaluate the model fit
− Calculate the PK/PD parameter
− Generate the reports
01) Import the data into the WinNonlin software: Import the data into the formats, including CVS,
Excel and Text Files.

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02) Selecting the appropriate pk/pd model: The type of pk/pd selected depends on the drug and the data
have. Some common model as follows:
- One compartment Model
- Two compartment Model
- Michaelis-Menten Model
- Emax. Model.
03) Fitting the model to data: WinNonlin uses variety of methods to fit the models to data, including
least squares methods & the maximum likelihood methods.
04) Evaluating the model fit: When fit the model to data, need to evaluate the model fit. This done by
locking at the residual plots and the R-squared values.
05) Calculating the pk/pd parameter: When evaluation had done of model fit, then calculate the pk/pd
parameters. These parameters tell the drug how much absorbed, distribute, metabolized and
eliminated.
06) Generating the reports: WinNonlin can generate a variety of reports in tables, graphs 7 figure. These
reports can use to communicate the result of analysis to others.
EXPERIMENTAL PROCEDURE: The procedure to determine the PK/PD in the software as following:
01. Import the Data: Open WinNonlin, click on the “file” menu & select the “import Data”.
- Select the “table” option & click on the “next button”.
- Select the CSV file that contains your data & click on the
“open” button.
- The data will be imported into the WinNonlin in a table.
Sr. No. Time (hr.) Concentration (mg/mL)
1 0 100
2 1 80
3 2 60
4 3 40
5 4 20
6 5 00

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02. Selecting the appropriate pk/pd model:
One compartment model: ADME of drug are rapidly absorbed & distributed throughout the body.
Two compartment model: ADME of drug are slowly absorbed & distributed throughout the body.
Michaelis Menten Model: The Relation between the drug conc. & response. It describes the rate of
enzymatic reaction.
Emax. Model: Similar to the Michaelis equation, describes the max. response that drug achieved.
Drug Type Appropriate pk/Pd Model Example
Rapidly
absorption/distribution
One compartmental model Aminoglycosides. Warfarin,
propranolol, insulin
Slowly
absorption/distribution
Two compartmental model Digoxin, phenytoin, theophylline
Drug with a clear dose
response relationship
Michaelis Menten equation Warfarin, penicillin,
acetylcholinesterase
Drug with an all-or-
none response
Emax. Aspirin, chlorpheniramine,
epinephrine and nifedipine
03. Fitting the Appropriate Model to data: Here some of the steps as follows:
a) Open WinNonlin software & create the new project: Go to “File”>New>Project. In the project
dialog box, select the modeling project type & click Ok.
b) Import the plasma conc. & time data into WinNonlin Software: Go to “File > Import. In the
import dialog box, select the one compartment model type & click Ok.
c) Create the One compartment model in WinNonlin Software: Go to Model > New Model. In
the new model dialog box., select the one compartment model & click Ok.
d) Fill the model to the using data the Non-Linear Regression tools in WinNonlin Software: Go
to model>, in the fit dialog bx, select the non-linear regression tab. In the model field, select the
one compartment model that, created in step. 3. In the data field, select the plasma conc. data that
you imported in step. 2, click Ok.
e) Evaluate the fit of model to data: Go to “View> Fit result, Fit the results the dialog box will
show you the result of non-linear regression fit. Evaluate the fit of model to data.

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f) Save the model & result.
04. Evaluating the Model Fit:
- Residual plots: Good randomly scattered around the line of zero.
- R- Squared Value: A high R2
Value (closer to 1) indicate- Good Fit.
- Low R2 Value (closer to 0) indicate – Poor fit.
- AIC/BIC: Lowest AIC/BIC mean best fit.
- Visual Inspection: Smooth Curve.
05. Calculating the PK/PD parameters:
- Cl = Dose/AUC
- Vd= AUC/Cmax. – AUC calculate by the go to.
- T1/2 = 1H (2)/Cl – “View> Area Under Curve”. The area under curve dialog box show
AUC for the fitted model.
06. Generating Reports: The reports generate d of Pk reports includes ADME of drug.
- PD reports for relationship between the drug plasma conc. & effect on blood
pressure.
- Safety reports.
Result: The PK/PD of given beta-blocker propranolol drug has been calculated & graph will plot carefully.
Pharmacokinetics parameters Value of parameters of drug
Cl 10L/h
Vd 50L (4L/kg)
Mean Plasma concentration 100mg/mL
Standard deviation 20mg/mL