2/7/13 Absorption and Disposition

U nivers ity home » Fac ulty of M edic al and H ealth Sc ienc es » Sc hool of M edic al Sc ienc es » P harmac ology » M E D SC I 7 1 9 » T imetable and res ourc es » A bsorption and disposition

School of Medical Sciences

Absorption and Disposition

Objectives

The objectives are:

1. Define common models of absorption using closed form solutions and differential equations.
2. Find out how to compare the fit of models to the same data.

Introduction
(collapse/expand)

Pharmacokinetic models have three main components:

1. Input: Drug inputs are commonly described as:

2. Bolus
3. Zero order (Tk0)
4. First Order (Tabs or Ka)

A lag time (Tlag) may be used with any of these input models.
1. Distribution: Most commonly defined in terms of the number of compartments. Distribution is usually a first order process. The key
parameters of distribution are the volumes of distribution (V1, V2…, Vss) for each compartment and inter-compartmental clearances
(Clic1,..) between the central compartment and peripheral compartments of a mammillary model.
2. Elimination: Drug elimination is characterised by models for clearance:

1. First-order (CL)
2. Mixed-order (Vmax, Km)

Absorption: definition and physiological determinants

Absorption is the name given to the process that determines how much of an administered drug enters the body. Absorption may be local or
systemic in terms of the physiological process and the resulting effects. Absorption kinetics generally describe the process of the drug entering
into the central compartment (circulation). Absorption is determined by multiple different processes, and is commonly described by two
factors: time independent = Extent (F) and time dependent = Rate.

Disposition
The term disposition is from the verb ‘to dispose’ or to get rid of. In pharmacology, disposition refers to what happens to the drug after it
enters the body, including distribution, and elimination processes. This encompasses clearance and accumulation (i.e. excluding absorption).

Bioavailability
The term bioavailability (F) refers to the extent of absorption. Bioavailability may be described by two processes: Fraction absorbed (f) and
First pass extraction ratio (ER). Fraction absorbed is determined by blood flow, the physiochemical properties governing diffusion, intraluminal
metabolism, and transport processes including secretion. ER is determined by organ blood flow and metabolism. The extent of absorption is
estimated as the area under the concentration time curve (AUC), and this is useful for comparing the bioavailability of generic drugs. AUC
values can also be used to determine initial values of parameters for first order processes of elimination (Clearance = CL = dose/AUC), and
absorption (Bioavailability = F = AUC test/AUC reference). AUC estimations can involve error due to extrapolation from beyond the last data
point, and so their accuracy is often limited by inadequate data (1, p. 67).

To convert an intravenous dose to an equivalent oral dose it is necessary to divide by bioavailability (F). For example, the bioavailibilty of oral
morphine varies from 15-30%. This equates to an IV:Oral dose ratio of 1:3 for chronic opiate users, and 1:6 for the opiate naive.

Absorption rate depends on the route of administration, the type of input, physiological processes (blood flow, gastric emptying),
physiochemical factors and drug formulation. There are 3 types of input processes describing rate of absorption: bolus, zero-order, or first
order. Bolus input implies instantaneous absorption. Zero order input means a constant rate of input, eg intravenous infusion. Repeated
intermittent oral dosing also achieves the same average steady state concentrations as a constant rate infusion, and accumulates at the
same rate, but with higher peak concentrations and swings between peak and trough concentrations. First order input absorption occurs at a
rate proportional to the amount of drug, and the rate changes with time, typically decreasing over time (eg. intramuscular, intestinal
absorption).

Absorption rate is by definition time dependant, and the term Tk0 is used to describe duration. Tmax (time to peak concentration) and Cmax
(peak concentration) are used to describe rate of absorption to allow comparison between generic medicines. Half life of absorption predicts
the time to peak concentration, and will be considered further in the next section.

The site of absorption of an oral preparation is an important consideration. Few drugs are absorbed in the stomach itself (with alcohol being an
exception). Most orally administered drugs are absorbed from duodenum, so that gastric emptying acts as a physiological control on the rate of
absorption and may effectively result in zero order infusion kinetics. Slow release formulations represent a pharmacological control mechanism

www.fmhs.auckland.ac.nz/sms/pharmacology/holford/teaching/medsci719/absorptionanddisposition/ 1/6
2/7/13 Absorption and Disposition
of rate of absorption that may also result in zero order input. Delays in drug absorption may be due to a variety of processes including gastric
emptying and formulation and can be coded in a model by describing the effect of lag time (Tlag).

Different considerations apply to non-intestinal sites of drug administration and absorption. Drugs can be administered by almost any route
imaginable, even intrapleural and intraperitoneal. Systemic absorption is usually the goal of rectal, buccal, subcutaneous and intramuscular
administration. Local absorption is usually the main objective of intraarticular, spinal, epidural, and topical (conjunctival, cutaneous, mucosal),
although some degree of systemic absorption may occur. Systemic absorption can occur from specific trancutaneous formulations (eg. nicotine
and Fentanyl patches). Rectal absorption processes can be particularly complex to predict depending on how much enters the portal
circulation and the impact of first pass metabolism.

Half life
Half life is the time taken for a first order process to be 50% complete. This process could be absorption, elimination or accumulation. The
natural logarithm of two (ln (2)) is used to calculate half life, and may be approximated to 0.7. In a first order process, an exponential function
predicts time course. After one half-life the process is 50% complete, after 2 half-lives 75%, 3 half-lives 87.5% , 4 half-lives 93.75%, 5 half-
lives 96.875 and so on. A first order process can be considered relatively complete after 4 half-lives.

Absorption half life is determined by Ln2/Ka, where Ka is the proportionality constant that relates drug amount and rate of absorption.
Absorption half lives are typically short eg. 30 minutes. Time to peak effect (Tmax) is approximately 3 x absorption half life, (where peak effect
is the effect at peak concentration).

Elimination or accumulation half-lives have the same time value, but describe different processes. In a simple one compartment model, half life
is determined by clearance and volume of distribution, T1/2= ln2*Vd/CL. In this way half life may be thought of as a proportionality constant
describing volume of distribution (Vd) and clearance (CL). Thus half life may not change despite changes in Vd and CL if they change
proportionally. It is often preferable to estimate clearance and volume as primary parameters, and then derive half life as a secondary
parameter.

Accumulation during constant infusion or intermittent oral dosing is time dependant and determined by half life. After one half life, a drug will
accumulate to 50% of steady state. Steady state will be reached after approximately 4 half-lives. Accumulation rate will be the same whether
a drug is given by repeated bolus doses or constant infusion as long as the same total amount of drug is administered over a given time period.
The rate of accumulation is the same, since rate = amount of drug/time, but there will be more peaks and troughs for bolus doses.

Accumulation for repeated doses is determined by dosing interval (dosint) and half life. This can be described by an equation for accumulation
factor: AF = 1/(1-EXP(-CL/Vd. Dosint))

If the dosing interval is equal to half life then the accumulation factor is 2, which means that the concentration at steady state is twice the
concentration after the first dose. So accumulation factor is the ratio of concentration at steady state to concentration after first dose. This
only applies at the same time after the dose, eg concentration measured 10 minutes after 1st dose, and 10 minutes after dose occurring at
steady state (4 half lives).

Elimination half life refers to the time for plasma concentration to reduce by 50% after the input stops. Elimination is usually a first order
process for most drugs, but may be mixed (eg. alcohol). Context sensitive half time (CSHT) is a concept that relates duration of infusion and
elimination processes once the infusion stops. It is influenced by the physiochemical properties of the drug and distribution as well as
clearance. It is often discussed with respect to prolonged infusions of lipid soluble drugs such as fentanyl in anaesthesia an intensive care
practice, but will not be considered further here.

Rate of input and output and differential equations

Models may be defined in different mathematical forms. Often the simplest analytical solution involves the use of closed form equations. Explicit
equations express the dependent variable as a function of the independent variable, constants and parameters of the model (1, p. 35). Implicit
equations include the dependent variable (eg. as initial drug concentration), for example Michaelis -Menten type processes (1, p. 38).

Differential equations are often required for iteration of more complex models. Differential equations describe the rate of change of a variable
with time. This is commonly expressed as d/dt (X), which is the differential of X with respect to time, where X is a dependant variable. Either
amount or concentration may be used, as long as this is consistent for the equation or series of equations. If amount is used, concentration
needs to be specified as amount/volume. The initial or starting amount or concentration of each variable needs to be specified for each
compartment considered.

The rate of change of a variable is equal to the inputs – outputs. At steady state the rate of input is equal to the rate of output. Rate of
input is described by administration method and absorption kinetics: bolus, zero order, or 1st order or a combination. Rate of output is
described by elimination models: 1st order or mixed order. Mixed order processes, incorporate both constant and maximum rate of a process.

As a form of mathematical description differential equations can be helpful for conceptualizing physiological processes and more complex
models e.g. effect compartments, combinations of different types of input, and multiple compartment models. Inter-compartmental clearance is
generally a first order process. The structural model and number of compartments is determined not only the properties of the drug, but from a
modelling perspective determined by the particular data. Different structural models (single or multiple compartments) may be required to give
the best fit for the particular data set. More complicated models are not necessarily more valid.

Differential equations are transformed by different methods to produce integrated equations. Pharmacometric software enables progressive
calculation of integrated values from differential equations. This can be time consuming for more complex models. Various different methods of
solving differential equations in a stepwise fashion exist, for example Runge-Kutta. Modifications of this method allow improved accuracy (eg.
determination of step size) (1, p. 53).

The use of nested conditional expressions (if then else endif blocks) within the model may allow the differential equations to be solved more
quickly. Examples in this assignment include expressions defining lag time and duration of input.

Evaluating a model: methods of comparing goodness of fit

How and why do we attempt to choose ‘the best model’ if all models are wrong? The ‘rightness’ of a model is a relative not absolute concept.

www.fmhs.auckland.ac.nz/sms/pharmacology/holford/teaching/medsci719/absorptionanddisposition/ 2/6
2/7/13 Absorption and Disposition
What is the main objective of the model? For example parameter estimation, covariate evaluation, or assessment of between subject
variability? The clinical relevance and applicability of the model is important in evaluating its usefulness, its ‘fit’ for purpose. Pharmacometrics
by definition entails measurement and quantification, but to some extent subjective evaluation is also important. Before embarking on model
building it is helpful to have clear objectives and a plan for evaluation.

A useful model describes a particular data set well, and best predicts and explains the relationship of the variables in the system. The simplest
methods of fitting mathematical models to data involve drawing a line of best fit through observed data points (e.g. ‘eyeball method’).
Pharmacometric modelling involves adjusting parameter estimates to best fit the model to the data (1, p. 11). During modelling, parameters are
determined by nonlinear regression. Parameters may be adjusted, added or subtracted. Constants remain fixed (doses, infusion times). The
stability of the model can be assessed by rerunning it with different initial parameter estimates. More complex models are not necessarily
better, and may involve more error. Evaluating a model is necessary to avoid overparameterisation.

Most simply model evaluation involves comparison between observed and predicted data (eg. concentration values), commonly represented in
graphical form. This is termed ‘Goodness of Fit’ (GOF). The characteristics of a model can be varied to predict values that are more likely to
reflect true population values. Of course the true population values can never be entirely known, but comparison with observed sample values
provides a reference. Simulation and bootstrapping are used to evaluate the robustness and sensitivity of the model.

The data set being modelled will determine the structure of the model, covariate selection, and parameter estimates. For example, different
models for the same drug may vary in the number of compartments, the covariates, and the parameter estimates. This is because different
data sets may vary in terms of the characteristics of the population sampled, the time course observed by sampling, and errors involved. So to
compare and discriminate between models the same data set must be used.

Evaluation of a model occurs throughout the modelling process to enable selection of the model, and inclusion of covariates. This involves the
assessment of the accuracy, precision and variability of the observed and predicted data and estimates. As well as checking the fit to the
data, evaluation includes assessment of parameter estimates, the influence of covariates and the estimation of error and variability. In
evaluating parameter estimates we consider estimates of their variability and error, comparison with literature values and consideration of
empirical models. Biological plausibility is also an important consideration in evaluating covariate selection.

Evaluation may be the most difficult part of the modelling process. There is no one optimal test of the validity of a model and a variety of
methods are generally used. In evaluating the fit of a model to the data, we need measures to describe both how well it fits, and how and
where it does not fit. These two concepts of ‘fit’ may require different methods of evaluation: ‘lack of fit’ as well as goodness of fit. So as well
as overall goodness of fit, model evaluation ideally involves specific diagnosis of what the problems are with the model, and where they exist.
Different parts of model need to be evaluated, for example the fixed and random effects with NONMEM.

The output of pharmacometric software programs provides a large array of information describing the fit of the data. Two main methods are
used to evaluate a model, and determine how well it fits the data set: using graphical representations and statistical assessment.

Graphs for evaluating models Scatter plots are commonly used to evaluate goodness of fit and to detect differences between models. GOF
plots are probably more important tools of model evaluation then statistical tests such as objective function. A model with a lower objective
function is not necessarily if better if there is no difference in goodness of fit or parameter estimates. Graphical assessment of models is useful
to diagnose ‘lack of fit’ and specifically where the problem is. Outliers can be identified from visual inspection, and there are different
approaches that may be used to deal with these deviations from expected values.

Some standard diagnostic plots

PRED, DV vs Time Graphs of observed and predicted values for the dependant variable (eg concentration) versus time area simple and powerful
tool. Consistent amplitude and shape of the data should be a feature if the model is a good fit.

PRED vs DV Graphs can be constructed of predicted vs. observed dependant variable (eg. concentration). If the fit is good data should be
clustered uniformly and closely around a line of unity. The time course is lost in this graph.

Visual predictive check. Posterior or visual predictive checks (VPC) compare predicted with observed data (comparing 95% prediction interval).
They are more complex to perform and involve simulation from final parameter estimates, then comparison of the distribution of observations
over time within the simulated distribution (95% CI). VPCs are a relatively new method of model evaluation but are arguably one of the most
robust forms of diagnostic assessment (2).

Statistical methods of model evaluation. A number of statistical parameters are generated by each nonlinear regression program. Statistical
tests commonly used to evaluate and discriminate between models include objective function values, standard error and coefficient of
variation. In general terms, the model with smallest numerical value of the test parameter (minimum value) represents ‘the best model’ for the
data, i.e. the best fit. The statistical significance levels are set in advance. For example a reduction in objective function of around 4% is
commonly used (approximately equivalent to p < 0.05).

Wings for NONMEM output provides a Coefficient of Variation (CV%) for each parameter, estimating its variability. High CV > 10 or 20% or wide
confidence intervals may result from under or overparameterization; or problems with the selection, error and number of data points (1, p. 96).
If the estimates of standard error are very small then they are of limited value due to the sensitivity of this method to changes in the means.

Methods of model evaluation

Correlation coefficients provide limited information about goodness of fit. Coefficients range from zero to one, with one indicating a perfect
correlation or fit. Good fits usually have high R values, but the inverse is not always true (3, p. 322). Correlation is less useful for nonlinear
methods, where values > 0.9 may be calculated despite a visually poor fit (1, p. 108). Another disadvantage of correlation is that is does not
provide any information about the absolute values.

Plots of residuals and weighted residuals can be helpful for choosing error models and for evaluating models, but are probably of limited value
when presented in isolation without the other GOF plots discussed above.

A residual is the difference between an observed and calculated value for the dependant variable (3, p. 345).

Residual = Yobs – Ycalc

www.fmhs.auckland.ac.nz/sms/pharmacology/holford/teaching/medsci719/absorptionanddisposition/ 3/6
2/7/13 Absorption and Disposition
RES vs PRED: This plot should include zero line and trend line. The shape of distribution of predicted response around residual zero line
suggests the error model: uniform shape suggests additive error model, fanning suggests proportional error model. The shape may also suggest
if a weighting scheme is needed to deal with overestimation of large concentrations and underestimation of small concentrations.

WRES vs PRED: The shape of distribution of predicted concentration response should be uniform around the residual = 0 line, and within 3 SD.

RES vs Time: May reveal regions not well explained by model, for example where data such as sampling time is missing.

WRES vs TIME: The plot of weighted residual vs. time should be randomly dispersed around the residual zero line.

WRES vs ID: This plot can be useful to assess outliers and their impact on the model.

Subjective evaluation may be as important as objective assessment of a model. Hence the ‘rightness’ of a model depends on the perspective
of the modeller, the population, and the purpose of the model. Other important considerations are the biological plausibility and the simplicity of
the model (parsimony principle).

Study design to ensure sampling optimizes the number and timing of data point collection may improve model fit and accuracy of parameter
estimation.

Where the results of goodness of fit of plots and statistical tests differ, more emphasis should be place on the graph of overlaying values of
predicted and observed concentrations versus time.

Subjective assessment remains important, especially when faced with conflicting information about goodness of fit. However visual perceptual
errors and bias can lead to errors in the interpretation of Goodness of fit plots.

Modelling involves the creation of a model that fits the particular data set.

Bonate “A model defines how you think your data were generated” (4, p. 1).
Introduction by Anita Sumpter (2008).

References

1. Bourne D. Mathematical Modeling of Pharmacokinetic Data. CRC Press, Boca Raton, 1995.
2. Nick Holford. The Visual Predictive Check – Superiority to Standard Diagnostic (Rorschach) Plots. PAGE 14. 2005; Abstr 738. URL:
www.page-meeting.org/?abstract=738
3. Schoenwald RD. Pharmacokinetics in Drug Discovery and Development. CRC Press, Boca Raton 2002.
4. Bonate PL. Pharmacokinetic-pharmacodynamic modelling and simulation. Springer, New York, 2005.

Workshop tasks

Note: All files should be loaded from and saved to your

Pharmacometrics Data\Absorption and Disposition folder for this
assignment.

Excel model simulation

Find the file Pharmacometrics Data\Absorption and Disposition\kak0.xls

1. Open kak0.xls with Excel.

2. Look at each of the 3 worksheets (ka1, ka1L, k01L).
3. Identify:
4. The model code
5. The model parameters
6. The independent variable

Berkeley madonna
(collapse/expand)

Closed Form Equation for Absorption Model

1. Open Berkeley Madonna shortcut in folder "Pharmacometrics Programs"

2. Add code to the Equations window defining the STARTTIMEand STOPTIME, the output interval (DTOUT), the model parameters and the
model equation (Figure 1).
3. Click on Run to run the model.
4. Save your model in your Absorption and Disposition folder with the name ka1.mmd
5. View a table of times and concentrations by clicking on the Table icon in the Run 1 graph window.

METHOD RK4
STARTTIME = 0
STOPTIME=10
DT = 0.02
DTOUT=1
Dose=100
CL=3

www.fmhs.auckland.ac.nz/sms/pharmacology/holford/teaching/medsci719/absorptionanddisposition/ 4/6
2/7/13 Absorption and Disposition
V=10
Tabs=1
KA=logn(2)/Tabs
Conc=Dose*Ka/V/(Ka-CL/V)*(EXP(-
CL/V*Time)-EXP(-Ka*Time))
Figure 1. Code for ka1.mmd
Differential Equation for Absorption Model

1. Save the ka1.mmd model with the new name ka1de.mmd.

2. Change the model code as shown in Figure 2.
3. Click on Run to run the model.
4. Save your model.
5. View a table of times and concentrations by clicking on the Table icon in the Run 1 graph window.

METHOD RK4
STARTTIME = 0
STOPTIME=10
DT = 0.02
DTOUT=1
Dose=100
CL=3
V=10
Tabs=1
Ka=logn(2)/Tabs
init(Gut)=Dose
init(Conc)=0
d/dt(Gut)= - Gut*Ka
d/dt(Conc)=(Gut*Ka - CL*Conc)/V

Figure 2. Code for ka1de.mmd

MONOLIX
(collapse/expand)

1. Open Monolix and create a New Project.

2. Create a new folder called "ka1 data" in your Absorption and Disposition folder. Export the TIMEand CONCdata from the ka1 simulation in
kak0.xls to .csv format (ka1.csv) and save in Absorption and Disposition\ka1 data\.

The column headers for all data files will be:

#ID TIME AMT DV

To remind yourself how to format this input file, click here to view a similar file you
created two weeks ago (opens in a new window).

When you are ready to work with the ka1L and k01L data, create new folders for each
and export the simulated data to these folders (ka1L data\ka1L.csv and k01L
data\k01L.csv).

3. In Monolix, click 'The data', locate your ka1.csv file and click open. Place a check in the 'Use header' box and click accept.
4. Click 'The structural model' to view the model library. Navigate to the PK library and select the oral1_1cpt_kaVCl model. Click accept.

For each of the three simulated data sets (ka1, ka1L and k01L), you will perform
parameter estimates with three models:

ka1 model: oral1_1cpt_kaVCl

ka1L model: oral1_1cpt_TlagkaVCl
k01L model: oral0_1cpt_TlagTk0VCl

5. Change the initial parameter estimates under Fixed effects.

You can find the appropriate initial parameter estimates in

kak0.xls

6. Set the residual error model to 'comb2'.

7. Set the 'Residual error parameters' to 1 and 0.1. These are the initial estimates for a combined additive and proportional residual error
model for concentration.
8. Save your MONOLIX workspace in your ka1 data folder with the model name you are using (e.g. ka1.mat)

After you have used all three models with the ka1 data, create a folder for the ka1L data

www.fmhs.auckland.ac.nz/sms/pharmacology/holford/teaching/medsci719/absorptionanddisposition/ 5/6
2/7/13 Absorption and Disposition
and then for the k01L data.

At the end of the assignment, you should have three data folders each containing three
Monolix workspaces.

9. Check the boxes next to 'Run' for 'Estimate the Population Parameters' , 'Estimate the Individual Parameters' , 'Estimate the Fisher
Information Matrix' , 'Estimate the Log Likelihood' and 'Display some results'.
10. Run the model by clicking 'Run'
11. When the estimation finishes click on 'Results Settings' then 'VPC'.
12. Look at the individual graphs and VPC to see how well the model and the final parameters fit the data.
13. Save the VPC plot as a pdf file in the Monolix KA1 results folder. You can copy and paste from the pdf file for your report.

14. View the final parameter estimates by clicking 'Last Results'. The parameter estimates are also displayed in the command prompt that
is behind the main Monolix window.
15. Repeat for ka1L and k01L data.

Take care to save each Monolix workspace with a name that will clearly identify, to you,
the model and data type. These instructions suggest doing so by using seperate folders
for each simulated data set, containing three models each.

Assignment

1. Discuss methods of comparing models for goodness of fit.

2. Find out what the AIC and BIC are (displayed in pop_parameters.txt in the results folder for each model).
3. Write up the results of parameter estimation using Monolix.
4. Compare the results of fitting the 3 sets of data (kak0!ka1, kak0!ka1l, kak0!k01l) using the 3 Monolix models (a total of 9 sets of
parameter estimation).

Top

www.fmhs.auckland.ac.nz/sms/pharmacology/holford/teaching/medsci719/absorptionanddisposition/ 6/6