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Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire OrganismPowerPoint Presentation

Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire Organism

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Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire Organism

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Pharmacokinetic Parameter Estimation of Drug Distribution in An Entire Organism

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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

Therapeutic Window

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

- 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

- 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.

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.

- 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.

Left Forelimb

Right Forelimb

Brain

Heart

Input

Heart

Output

Stomach + Intestines

Liver

L. Kidney

R. Kidney

L. Hindlimb

R. Hindlimb

Tail

Lumped Other

Left Forelimb

Right Forelimb

Brain

Heart

Output

Heart

Input

Stomach + Intestines

Liver

L. Kidney

R. Kidney

L. Hindlimb

R. Hindlimb

Tail

Lumped Other

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

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

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.

- 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

9

Dosage [μg/ml]

6

3

2

4

6

8

Duration of injection [hr]

- 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.

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

Individual

Weight

Age

- Develop biochemical, anatomical and physiological (BAP) scaling laws.
- Create a library of models for animals commonly used in typical drug trials.