Package Rivivc

February 19, 2015

Type Package
Title In vitro in vivo correlation linear level A
Version 0.9
Date 2012-10-03
Depends signal, compiler
Suggests graphics
Description This package is devoted to the IVIVC linear level A with
numerical deconvolution method. The latter is working for
inequal and incompatible timepoints between impulse and
response curves. A numerical convolution method is also
available. Application domains include pharamaceutical industry
QA/QC and R&D together with academic research.
License GPL (>= 3)
Author Aleksander Mendyk [aut, cre], Sebastian Polak [aut]
Maintainer Aleksander Mendyk <[email protected]>
Repository CRAN
Date/Publication 2012-10-05 05:37:51
NeedsCompilation no

R topics documented:
Rivivc-package
impulse . . . .
input . . . . . .
NumConv . . .
NumDeconv . .
resp . . . . . .
RivivcA . . . .

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impulse

Rivivc-package

IVIVC LEVEL A

Description
This package performs linear iv vitro in vivo correlation of linear level A. It provides numerical convolution/deconvolution procedures with unequal time steps and no assumptions about the function
shapes.
Details
Package:
Type:
Version:
Date:
License:

Rivivc
Package
0.9
2012-10-03
GPLv3

Author(s)
Aleksander Mendyk and Sebastian Polak
Maintainer: Aleksander Mendyk <[email protected]>
References
Langenbucher (2003) F. Handling of computational in vitro/in vivo correlation problems by Microsoft Excel: III. Convolution and deconvolution. Eur J Pharm Biopharm. 56, 429-37.

impulse

PK profile after drug intravenous administration

Description
This data set gives the time and concentration of the hypothetical drug after its intravenous administration. This is the simulated data set.
Usage
impulse
Format
matrix

input

input

In vivo absorption of the drug

Description
This data set gives the time and cumulative amount of the hypothetical drug absorbed. It is also
used as in vitro dissolution for Rivivc example of IVIVC level A. This is the simulated data set.
Usage
input
Format
matrix

NumConv

Numerical convolution

Description
Performs numerical convolution independent of the sampling points but requiring the same timescale
of the input and impulse profiles.
Usage
NumConv(impulse.matrix, input.matrix, conv.timescale = NULL, explicit.interpolation = 1000)
Arguments
impulse.matrix matrix of the PK profile after the drug intravenous (i.v.) administration
input.matrix
cumulative in vivo absorption profile
conv.timescale a timescale of convolution defined either as a whole vector with specific timepoints c(t1,t2,...tN) or two-element vector containing only lower and upper
boundery of the required prediction timescale c(lower,upper); in the latter
case system creates the time vector based on the parameter explicit.interpolation;
if omitted it computes convolution timescale based on the input matrix
explicit.interpolation
sampling accuracy used by the interpolation method to find the same timepoints
for input and impulse profiles
Value
Output values are:
$par
$par_explicit

convolved time profile based on the original timescale

provides convolution with the explicit interpolation

NumDeconv

Author(s)
Aleksander Mendyk and Sebastian Polak
See Also
NumDeconv,
Examples
require(Rivivc)
require(graphics)
#i.v. data
data("impulse")
#p.o. PK profile
data("resp")
#in vitro dissolution for correlation purposes
data("input")
#preparing data matrices
input_mtx<-as.matrix(input)
impulse_mtx<-as.matrix(impulse)
resp_mtx<-as.matrix(resp)
#setting interpolation accuracy
accur_explic<-1000
#run convolution
result<-NumConv(impulse_mtx,input_mtx,explicit.interp=accur_explic)
print("Raw results")
print(result$par)
print("Raw results explicit")
print(result$par_explicit)
dev.new()
plot(resp_mtx)
lines(result$par, type="l", col="blue")
dev.new()
plot(resp_mtx)
lines(result$par_explicit, type="l", col="blue")

NumDeconv

Numerical deconvolution method

NumDeconv

Description
Numerical deconvolution method based on the convolution and the optim() BFGS method to find
in vivo absorption profile through the convolution approach. The function works iteratively with
the cumulative in vivo absorption profile optimization performed by the BFGS method in regard to
the convolved PK profile and its proximity to the real known p.o. profile.
Usage
NumDeconv(impulse.matrix, resp.matrix, dose_iv=NULL, dose_po=NULL,
deconv.timescale = NULL, explicit.interpolation = 20,
implicit.interpolation = 10, optim.maxit = 200)
Arguments
impulse.matrix matrix of the PK profile after the drug intravenous (i.v.) administration
resp.matrix

PK profile after oral (p.o.) administration of the drug

dose_iv

drug dose after i.v. administration; not obligatory but if provided must be in the
same units like the dose p.o.

dose_po

drug dose after p.o. administration; not obligatory but if provided must be in the
same units like the dose i.v.
deconv.timescale
a timescale of deconvolution defined either as a whole vector with specific timepoints c(t1,t2,...tN) or two-element vector containing only lower and upper
boundery of the required prediction timescale c(lower,upper); in the latter
case system creates the time vector based on the parameter explicit.interpolation;
if omitted it computes deconvolution timescale based on the impulse matrix
explicit.interpolation
deconvolution explicit interpolation parameter, namely number of the curve interpolation points used directly by the optim() method
implicit.interpolation
implicit interpolation - a factor multiplying explicit.interpolation for better accuracy
optim.maxit

maximum number of iterations used by optim() method

Details
This method is an empirical approach to the deconvolution method with minimum mechanistic
assumptions. Yet the latter involve kinetics linearity when the doses of i.v. and p.o. are different,
thus the i.v. profile is scaled by multiplication with the factor of dose_po/dose_iv. It is also
important to know that large values of explicit and/or implicit accuracy lead to the long execution
times. The recommended values are explicit = 20 and implicit = 10, however this is only
a rule of thumb used here. When looking for higher accuracy it is advisable to increase implicit
interpolation prior to the explicit.

NumDeconv

Value
Three matrices are returned at the output of the function:
$par

represents original timescale provided at the input

$par_explicit

provides deconvolution with the explicit interpolation

$par_implicit

provides deconvolution with the implicit interpolation

Author(s)
Aleksander Mendyk and Sebastian Polak
See Also
RivivcA
Examples
require(Rivivc)
require(graphics)
#i.v. data
data("impulse")
#p.o. PK profile
data("resp")
#in vitro dissolution for correlation purposes
data("input")
#preparing data matrices
input_mtx<-as.matrix(input)
impulse_mtx<-as.matrix(impulse)
resp_mtx<-as.matrix(resp)
#setting accuracy for both interpolation modes
accur_explic<-10
accur_implic<-5
#for deconvolution
result<-NumDeconv(impulse_mtx,resp_mtx,explicit.interp=accur_explic,implicit.interp=accur_implic)
print("Raw results")
print(result$par)
print("Explicit interpolation")
print(result$par_explicit)
print("Implicit interpolation")
print(result$par_implicit)

resp

#let's compare the deconvolved curve with known input

dev.new()
plot(input_mtx)
lines(result$par, type="l", col="blue")

resp

PK profile after drug oral administration

Description
This data set gives the time and concentration of the hypothetical drug after its oral administration.
This is the simulated data set.
Usage
resp
Format
matrix

RivivcA

Level A linear correlation for a single formulation

Description
This is the major function to be called where numerical convolution ad/or deconvolution might
be used for a linear in vitro in vivo correlation level A. It performes either numerical convolution via /codeNumConv() or deconvolution via /codeNumDeconv() and correlates their results
with the known.data object via linear regression lm(). If you just want raw results of convolution/deconvolution then call explicitely NumConv or link{NumDeconv}
Usage
RivivcA(known.data, impulse.data, second.profile.data,dose_iv=NULL,dose_po=NULL,
mode = "deconv", explicit.interp = 20, implicit.interp = 10,
optimization.maxit = 200)

RivivcA

Arguments
known.data

the data matrix to be correlated with; depending on the state of the mode variable
it represents either in vitro dissolution profile (mode = "deconv") or PK profile
after oral administration of the drug (mode="conv")

impulse.data
matrix of the PK profile after the drug i.v. administration
second.profile.data
matrix of the second PK profile; depending on the mode variable it represents
either PK profile after oral administration of the drug (mode = "deconv") or
a drug cumulative absorption profile (mode="conv"), sometimes substituted directly by the in vitro dissolution profile
dose_iv

drug dose after i.v. administration; not obligatory but if provided must be in the
same units like the dose p.o.

dose_po

drug dose after p.o. administration; not obligatory but if provided must be in the
same units like the dose i.v.

mode

represents the method used here; two states are allowed: mode="conv" for numerical convolution method or mode="deconv" for numerical deconvolution
(default)

explicit.interp
convolution and deconvolution explicit interpolation parameter, namely number
of the curve interpolation points
implicit.interp

implicit interpolation - a factor multiplying explicit.interp for better accuracy; applies to the deconvolution procedure only
optimization.maxit
maximum number of iterations used by optim() method; applies to the deconvolution procedure only
Details
The function represents either convolution or deconvolution data together with linear regression
of the above functions outputs and known data supplied as a parameter. Please bear in mind that
NumDeconv() procedure is iterative and therefore depending on the parameters might require substantial amount of time to converge. Please refer to the NumDeconv description.
Value
$regression

returns a whole object of the linear regression - a result from the lm() procedure

$numeric

returns results from NumConv() or NumDeconv() functions

Author(s)
Aleksander Mendyk and Sebastian Polak
See Also
NumConv, NumDeconv

RivivcA

Examples
require(Rivivc)
require(graphics)
#i.v. data
data("impulse")
#p.o. PK profile
data("resp")
#in vitro dissolution for correlation purposes
data("input")
#preparing data matrices
input_mtx<-as.matrix(input)
impulse_mtx<-as.matrix(impulse)
resp_mtx<-as.matrix(resp)
#setting accuracy
accur_explic<-20
accur_implic<-5
#run deconvolution
result<-RivivcA(input_mtx,impulse_mtx,resp_mtx,explicit.interp=accur_explic,implicit.interp=accur_implic)
summary(result$regression)
print("Raw results of deconvolution")
print(result$numeric$par)
predicted<-predict(result$regression)
deconvolved_data<-unname(predicted)
orig_data<-input_mtx[,2]
dev.new()
plot(orig_data,result$numeric$par[,2])
lines(orig_data,deconvolved_data, type="l", col="blue")
dev.new()
plot(input_mtx)
lines(result$numeric$par, type="l", col="blue")

Index
Topic IVIVC Level A
RivivcA, 7
Topic NumConv
NumConv, 3
Topic NumDeconv
NumDeconv, 4
Topic RivivcA
RivivcA, 7
Topic convolution
NumConv, 3
Topic datasets
impulse, 2
input, 3
resp, 7
Topic deconvolution
NumDeconv, 4
Topic package
Rivivc-package, 2
impulse, 2
input, 3
NumConv, 3, 7, 8
NumDeconv, 4, 4, 8
resp, 7
Rivivc (Rivivc-package), 2
Rivivc-package, 2
RivivcA, 6, 7

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