Part 7 Pharmacokinetic and Metabolic Examples

Design and Analysis of Modeling Studies Resource Facility for Population Kinetics and SAAM Institute, Inc. University of Washington, Seattle, WA

Pharmacokinetic Models

Outline
How to set up in SAAM II some specific pharmacokinetic models:
Linear 1, 2 and 3-compartment iv and/or first order absorption, with and without lags, with clearance or rate constant parameterization

Importance of different parameterizations (rate constant and clearance) and of delay compartments. Estimating standard PK parameters from a multicompartmental model

Primary and Secondary Parameters

We have discussed only parameter estimation as it relates to a given models parameters. How can we estimate the PK parameters we want (in addition to the model parameters)? What about reparameterizing the model?

Primary and Secondary Parameters

For a linear compartmental model, the primary parameters are the volumes and the rate constants k(i,j). Secondary parameters are functions of these primary parameters. All of the desired PK parameters can be written in terms of the primary parameters.

Primary and Secondary Parameters

s1=q2/vol2 k(2,1) k(3,2) k(2,3) k(0,2)

1
k(0,1)

clearance = k(0,2)*vol2 kabs = k(2,1) bioavailability = k(2,1)/(k(2,1)+k(0,1))

Model Reparameterization
Rate constants to clearances Writing the k(i,j) in terms of desired PK parameters.
s1=q2/vol2 3 1 k(2,1) k(3,2) 2 k(2,3) k(0,2)

k(0,1)

Example: In this model, it is possible to write k(0,2) as a clearance term.

Model reparameterization
Clearances to rate constants Requires keeping track of how to change all rate constants in the model. Relatively simple for one, two compartment models, difficult for more complex models. Can be situations when it may not work (e.g. losses occur from several compartments). Has advantages and disadvantages, but should be used with care. Sometimes easier to write the desired parameters in terms of primary model parameters.

Two-compartment model + absorption

s1=qc/Vc Ka Kcp c Kel p Kpc

a Kel Vc Kcp Kpc Ka

Primary

Derived

CLt = Kel*Vc CLd = Kcp*Vc Vp = Vc*Kcp/Kpc

Two-compartment model + absorption

s1=qc/Vc Ka

a CLt Vc CLd Vp Ka

c CLt

CLd

Primary

Derived

Kel = CLt/Vc Kcp = CLd/Vc Kpc = CLd/Vp

Models of Metabolic Systems

Some Metabolic Models Using SAAM II

Applications to lipoproteins, intermediary metabolism, trace elements and minerals. In the Compartmental Tutorials description Some information on radioactive and stable isotopes

Useful References
Barrett, PHR, BM Bell, C Cobelli, H Golde, A Schumitzky, P Vicini and DM Foster. SAAM II: Simulation, analysis and modeling software for tracer and pharmacokinetic studies. Metabolism 47: 484-492, 1998 Foster, DM. Developing and testing integrated multicompartmental models to describe single-input multiple output study using the SAAM II software system. Advances in Experimental Medicine and Biology 445: 59-78, 1998 Cobelli, C and DM Foster. Compartmental Models: Theory and Practice Using the SAAM II Software System. Advances in Experimental Medicine and Biology 445: 79-102, 1998

Models of LDL Metabolism Kinetic Heterogeneity

Foster, DM, A Chait, JJ Albers, C Harris and JD Brunzell. Evidence for kinetic heterogeneity among human low density lipoproteins. Metabolism 35:685-696, 1986

System Model Structure

LDL Model

I/O Definition

Sample Equation

Exogenous Input: Split Input

Split Input Equation

Balance of Mass

There is no k(0,13)

Balance of Mass

Equations balance loss from compartment 13

Model Predictions

Multiple Input/Output Studies: Ketone Bodies

Cobelli C., Nosadini R., Toffolo G., McCulloch A., Avogaro A., Tiengo A., Alberti K.G.M.M.: Model of the kinetics of ketone bodies in humans. Am. J. Physiol. 243: R7-R17, 1982.

System Model

Example Data Set

Experimental Protocol
Co-inject C-14 leucine and 3-H KIC. Plasma measurements of C-14 leucine and KIC,and 3-H leucine and KIC

Leucine Injection and Samples

KIC Injection and Samples

Multiple Tracer Experiments

Multiple Tracer Experiments

Model Equations

Model Predictions

Partly Compartmental Flow Models: Glucose Kinetics

Jacquez, J.A., "Compartmental analysis in biology and medicine - 3rd Edition", BioMedWare, Ann Arbor, MI 1996, Chapters 9 and 10.

System Model(s)

Injection and Sampling

Duplicating Models

Duplicating Models

Transfer Rates

Parameters

Reference (vascular) marker

Test (extracellular) marker

Radioactive and Stable Isotopes

Useful References for Stable Isotopes

Foster, DM, PH Barrett, C Cobelli, G Toffolo and W Beltz. Estimating the fractional synthetic rate of plasma apoproteins and lipids from stable isotope data. J. Lipid. Res. 34:2193-2205, 1993 Toffolo, G, DM Foster and C Cobelli. Estimation of protein fractional synthetic rates from tracer data. Am. J. Physiol. 264: E128-E135, 1993

Radioactive vs. Stable

RADIOACTIVE TRACER STABLE TRACER

TRACEE (natural)

a M

s M

a M

s M

TRACER (infusate)

r d

a d

s d

SAMPLE

a M

s M

r m (t)

a a M + m (t)

s s M + m (t)

Measurement Variable
Radioactive tracer: concentration or specific activity. Stable isotopes: isotope ratio, abundance or enrichment Enrichment is not the equivalent of specific activity

Enrichment vs. TTR

0.25 r(t) 0.20 a(t) 0.15 e (t) 2 z(t)

0.10

e (t) 1

0.05

0.05

0.10 r(t)

0.15

0.20

0.25

Correct Measurement Variable for Stable Isotopic Tracers is the Tracer-Tracee Ratio
Tracer-tracee ratio, called z(t), measures for each sample the quotient of the amount of tracer and tracee in the sample Requires a formula to convert from the standard measurement variable to z(t).

How do standard measurements relate to TTR?

Conversion of Measurement Variables

Use a spreadsheet Can copy the results directly into SAAM II

Setting Up Model
Assuming the steady state, create a normal tracer-tracee model. Know the input of tracer into the tracer model Measurement variable qi(t)/Qi will automatically calculate the tracer-tracee ratio

Practical Issues in Experimental Design with Stable Isotopes

Normally a precursor-product situation Time of the experiment can be critical

Precursor-Product

Precursor Recycling?

Product - Model?

Duration of Experiment
Information from radioactive tracer experiments carried over to stable isotope experiments? What is known about the time line for the metabolism of a substance?

Model Prediction (14 days)

Model Prediction (1.5 days)

Model Prediction (1.5 days)

What is Happening?
14 day 36 hour