Pharmacokinetic parameter estimation of drug distribution in an entire organism
This presentation is the property of its rightful owner.
Sponsored Links
1 / 14

Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire Organism PowerPoint PPT Presentation


  • 86 Views
  • Uploaded on
  • Presentation posted in: General

Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire Organism. Eric Lueshen, Cierra Hall, Andrej Mošať and Andreas Linninger University of Illinois at Chicago, Department of Bioengineering 2010 AIChE Annual Meeting November 11, 2010. Therapy Design Case Study: Cyclosporin A.

Download Presentation

Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire Organism

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Pharmacokinetic parameter estimation of drug distribution in an entire organism

Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire Organism

Eric Lueshen, Cierra Hall, Andrej Mošať and Andreas Linninger

University of Illinois at Chicago, Department of Bioengineering

2010 AIChE Annual Meeting

November 11, 2010


Therapy design case study cyclosporin a

Therapy DesignCase Study: Cyclosporin A

Therapeutic Window

Effect of drug administration method for same dosage (6 mg/kg).


Deficiencies with classical pharmacokinetics

Deficiencies with Classical Pharmacokinetics

  • Data fitting and black-box models.

  • Results are hard to scale.

  • No mass conservation.

  • Equations sometimes based on unobservable phenomena such as specific binding.

  • Derive very little information in terms of drug kinetics and biotransport phenomena.

Rigorous engineering approach needed for the development of Physiologically-Based Pharmacokinetic (PBPK) models to address these deficiencies.

Black-box


Specific aims

Specific Aims

  • Develop an automated methodology for the rigorous assessment of a multivariate Physiologically-Based Pharmacokinetic (PBPK) model of an organism such as a rat based on first principles.

  • Apply the developed methodology towards improved scaling which can account for pathological conditions and differences in individual body composition.


Methodology for discovering transport kinetic parameters

Methodology for Discovering Transport & Kinetic Parameters

Observe Physical Phenomena

  • Obtain experimental data.

  • Construct closed vasculature

    flow network.

Create a PBPK Model

Discover Kinetics

  • Compute steady state blood

  • flow rates and pressures.

  • Select organ-specific PBPK

  • model and generate equations.

  • Estimate parameters via

  • kinetic inversion.

  • Optimize transport and

  • kinetic parameters.

  • Evaluate quality of each

  • PBPK model.


Step 1 bioaccumulation of cyclosporine a in different organs

Step 1: Bioaccumulation of Cyclosporine A in Different Organs

  • Male Sprague Dawley Rats

  • 277 +/- 15 g

  • 2 minute bolus injection into femoral vein

  • 12 organs & blood measured

  • 3 dose groups:

    • 1.2, 6, 30 mg/kg

1. Tanaka, et al. Drug Metabolism and Disposition, 2000.


Step 2 construction of the closed vasculature flow network for each analyzed species

Step 2: Construction of the Closed Vasculature Flow Network for each Analyzed Species

Left Forelimb

Right Forelimb

Brain

Heart

Input

Heart

Output

Stomach + Intestines

Liver

L. Kidney

R. Kidney

L. Hindlimb

R. Hindlimb

Tail

Lumped Other


Step 3 compute steady state flow rates pressures

Left Forelimb

Right Forelimb

Brain

Heart

Output

Heart

Input

Stomach + Intestines

Liver

L. Kidney

R. Kidney

L. Hindlimb

R. Hindlimb

Tail

Lumped Other

Step 3: Compute Steady State Flow Rates & Pressures

Constituitive Equations

Flow is conserved throughout the model

Pressure drops are proportional to volumetric flow rate

Hagen-Poiseuille equation

mmHg

MAP = 104 mmHg

MVP = 2 mmHg


Step 4 organ specific pbpk model equation generation

Step 4: Organ-Specific PBPK Model & Equation Generation

CyA clearance into metabolite:

Kidney:

Mass transfer into/from tissue:

Drug clearance:

Blood compartments:

Tissue bound drug compartments:

Hct: Hematocrit

CyA: Cyclosporin A

CyAT: Cyclosporin A bound to Tissue

MCyA: Metabolized Cyclosporin A


Step 5 parameter estimation via kinetic inversion

Step 5: Parameter Estimation via Kinetic Inversion

Objective function for space xj time tj

Conservation balances:

Optimization

of k-values

Satisfactory

Unsatisfactory

Global Solution

2. W. Tang, et al. Industrial and Engineering Chemistry Research, 2005.

3. M. Somayaji, et al. Computers and Chemical Engineering, 2008.


Step 6 solution of the kinetic inversion problem

Step 6: Solution of the Kinetic Inversion Problem

  • Kinetic rates (hr-1) - 9 of 30

  • kmuscle = 47.18

  • kskin = 54.03

  • kspleen = 35.22

  • kfat = 96.11

  • kgut = 31.20

  • kheart = 27.58

  • kliver = 118.04

  • kkidney = 70.09

  • kbrain = 7.03


Optimal therapy selection

Optimal Therapy Selection

9

Dosage [μg/ml]

6

3

2

4

6

8

Duration of injection [hr]


Knowledge gain

Knowledge Gain

  • First principles kinetics allows model to be scalable.

    • Determines the global transport mechanisms of drugs based on biochemical, anatomical, and physiological data.

      • Information is able to be derived from experimental data.

      • No longer reliant on pure data fitting.

  • Conservation of mass ensures model fidelity.

  • Accurate prediction of dose curves.

  • Variety of therapy designs including administration mode (oral, intravenous; bolus, continuous), dosage interval, concentration and total drug amount.


Future plans

Individual

Weight

Age

Future Plans

  • Develop biochemical, anatomical and physiological (BAP) scaling laws.

  • Create a library of models for animals commonly used in typical drug trials.


  • Login