Work Flow

With the development and application of pharmacokinetic analysis software and computer technology, the methodology of PK/PD model establishment has also made great progress. Here is the use of 5 steps for modeling methodology research.

• Preliminarily determine the experimental model based on the dose and pharmacodynamic index pre-test. Establish the "concentration-effect" relationship and determine the preliminary model of the "dose-effect" relationship.
• Carry out a reasonable experimental design to determine the drug dosage, sampling time, and monitoring effect time.
• Obtain corresponding data in formal experiments.
• Conduct preliminary research on experimental data by drawing concentration-time, effect-time and concentration-effect diagrams. Verify and improve the model determined in the pre-test.
• The model is finally determined through the above research. Obtain the PK/PD parameters by fitting experimental data, and realize the evaluation and analysis of the experimental results.

PK/PD Modeling Results

The PK/PD model obtains the following information by measuring the data of "blood drug concentration-time-effect":

• A series of pharmacokinetic parameters of the drug in animals or humans.
• Infer the concentration of the drug at the effect site and quantitatively reflect the dose-effect relationship, thereby giving a series of pharmacodynamic parameters. From the three-dimensional graph of "blood drug concentration-time-effect", formulate a reasonable dosing plan and clarify the effect of hysteresis.
• Clarify the abnormal drug efficacy caused by factors such as long-term drug use, gender, age, combined drug use, and disease conditions. Analyze the functional mechanism of drug through changes in pharmacokinetic and pharmacodynamic parameters.

PK/PD Modeling Analysis Programs

The calculation methods of linear pharmacokinetic parameters mainly include: Simplex method, Gauss-Newton iteration method, and improved Gauss-Newton iteration methods such as Marquardt method and Hartley method. Among them, Marquardt method and Hartley method are the most commonly used. Many pharmaceutical programs include pharmacodynamic models, such as linear models, logarithmic models, and Sigmoid models (Hill’s equation). The logarithmic model is often used for microbial determination, and the Sigmoid E_max model can better describe most S-type dose-response relationships. There are several commonly used PK/PD model analysis programs at present.

• NONLIN series PK/PD programs (NONLIN, PCNONLIN and WINNONLIN)
  The program can calculate and analyze:
  
  • 1) Compartmental modelling. Deal with various nonlinear regression problems; parameter estimation; solving various differential equations; simulating the changes in efficacy of different medication schemes or after parameter adjustments. Providing a wide range of model libraries, which can solve various model fitting problems, including pharmacokinetic model, pharmacodynamic model, indirect response model and PK/PD joint model, custom model, etc. Use dynamic memory management technology to handle large data and complex models.
  • 2) Non-compartmental analysis: AUC_0~n， AUC_0~∞，C_max and other parameters can be calculated from blood or urine data. Calculate parameters of steady-state data. Terminal elimination phase can be selected in semi-logarithmic diagram or automatically selected by the program. Calculate AUC at any end point, etc.
• ADAPTⅡ
  ADAPTⅡ(Version 4). The model library of ADAPTⅡ has 37 different types of models, including 16 PK models, 8 PK/PD combined models, and 13 special models.
• PH/EDSIM (Mediware)
  The PH/EDSIM program is a general processing tool of PK/PD model. The program is flexible to use and allows the operator to design model in the form of graphs, instead of programming. PK model, PD model or PK/PD combined model designed by this program can be used for prediction or fitting.
• JGuiB
  JGuiB is a program written in Java language and has been upgraded to JGuiB 3.0. The software enters the GUI-based application system from the boomer in the menu mode. JGuiB mainly includes three PK/PD models: normal fitting, simulation and Bayesian estimation. JGuiB can simultaneously fit several PK/PD models designed with different weights for a set of data (a program file can run up to 4 types). Bayesian estimation can be used for clinical pharmacokinetic services.

The preclinical applications of PK/PD model include:

• Screen the most effective compounds from many candidate compounds.
• Predict clinical effects (EC50).
• Provide guidance for early clinical trials.
• Provide guidance for setting the best sampling point.
• Screen the most effective compounds from many candidate compounds.
• Estimate the safety range based on the concentration of the target tissue
• Predict the oral bioavailability
• Predict the liver clearance.
• Estimate the possible drug interactions.

The PK/PD model can be used to predict the pharmacokinetic process of a new drug before in vivo testing. It helps to better analyze the characteristics of the pharmacokinetic model of the new drug, and establish a reasonable PK/PD model to assist the clinic in making drug screening decisions. Speculate the route of administration and dosage. CD ComputaBio has formed a team of experts excellent in PK/PD modeling, providing AI-driven solutions according to your detailed requirements.