Limits...
The use of a physiologically based pharmacokinetic model to evaluate deconvolution measurements of systemic absorption.

Levitt DG - BMC Clin Pharmacol (2003)

Bottom Line: The 11-compartment PBPK model is accurately described by either a 2 or 3-exponential function, depending on whether or not there is significant tissue binding.For noisy data, a gamma distribution deconvolution provides the best result if the input has the form of a gamma distribution.For other input functions, good results are obtained using deconvolution methods based on modeling the input with either a B-spline or uniform dense set of time points.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology University of Minnesota, Minneapolis, MN 55455, USA. levit001@umn.edu

ABSTRACT

Background: An unknown input function can be determined by deconvolution using the systemic bolus input function (r) determined using an experimental input of duration ranging from a few seconds to many minutes. The quantitative relation between the duration of the input and the accuracy of r is unknown. Although a large number of deconvolution procedures have been described, these routines are not available in a convenient software package.

Methods: Four deconvolution methods are implemented in a new, user-friendly software program (PKQuest, http://www.pkquest.com). Three of these methods are characterized by input parameters that are adjusted by the user to provide the "best" fit. A new approach is used to determine these parameters, based on the assumption that the input can be approximated by a gamma distribution. Deconvolution methodologies are evaluated using data generated from a physiologically based pharmacokinetic model (PBPK).

Results and conclusions: The 11-compartment PBPK model is accurately described by either a 2 or 3-exponential function, depending on whether or not there is significant tissue binding. For an accurate estimate of r the first venous sample should be at or before the end of the constant infusion and a long (10 minute) constant infusion is preferable to a bolus injection. For noisy data, a gamma distribution deconvolution provides the best result if the input has the form of a gamma distribution. For other input functions, good results are obtained using deconvolution methods based on modeling the input with either a B-spline or uniform dense set of time points.

Show MeSH
"Binding" PBPK model with exact data sampled at low resolution using 3-exponential response function. Same as figure 6 except the data was sampled at the "low" resolution time points.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC153531&req=5

Figure 7: "Binding" PBPK model with exact data sampled at low resolution using 3-exponential response function. Same as figure 6 except the data was sampled at the "low" resolution time points.

Mentions: For the 30-second constant infusion using the binding model (left hand column, figs. 4 to 8), the venous concentration predicted using r(t) for the times preceding the first experimental time point (2.5 minutes for high resolution, 10 minutes for low resolution) differs markedly from the true, model venous concentration. The corresponding error in the intestinal absorption rate is small when the first data point is at 2.5 minutes (high resolution data, figs. 4 and 6), but becomes large when the first point is at 10 minutes (low resolution data, figs. 5 and 7).


The use of a physiologically based pharmacokinetic model to evaluate deconvolution measurements of systemic absorption.

Levitt DG - BMC Clin Pharmacol (2003)

"Binding" PBPK model with exact data sampled at low resolution using 3-exponential response function. Same as figure 6 except the data was sampled at the "low" resolution time points.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC153531&req=5

Figure 7: "Binding" PBPK model with exact data sampled at low resolution using 3-exponential response function. Same as figure 6 except the data was sampled at the "low" resolution time points.
Mentions: For the 30-second constant infusion using the binding model (left hand column, figs. 4 to 8), the venous concentration predicted using r(t) for the times preceding the first experimental time point (2.5 minutes for high resolution, 10 minutes for low resolution) differs markedly from the true, model venous concentration. The corresponding error in the intestinal absorption rate is small when the first data point is at 2.5 minutes (high resolution data, figs. 4 and 6), but becomes large when the first point is at 10 minutes (low resolution data, figs. 5 and 7).

Bottom Line: The 11-compartment PBPK model is accurately described by either a 2 or 3-exponential function, depending on whether or not there is significant tissue binding.For noisy data, a gamma distribution deconvolution provides the best result if the input has the form of a gamma distribution.For other input functions, good results are obtained using deconvolution methods based on modeling the input with either a B-spline or uniform dense set of time points.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology University of Minnesota, Minneapolis, MN 55455, USA. levit001@umn.edu

ABSTRACT

Background: An unknown input function can be determined by deconvolution using the systemic bolus input function (r) determined using an experimental input of duration ranging from a few seconds to many minutes. The quantitative relation between the duration of the input and the accuracy of r is unknown. Although a large number of deconvolution procedures have been described, these routines are not available in a convenient software package.

Methods: Four deconvolution methods are implemented in a new, user-friendly software program (PKQuest, http://www.pkquest.com). Three of these methods are characterized by input parameters that are adjusted by the user to provide the "best" fit. A new approach is used to determine these parameters, based on the assumption that the input can be approximated by a gamma distribution. Deconvolution methodologies are evaluated using data generated from a physiologically based pharmacokinetic model (PBPK).

Results and conclusions: The 11-compartment PBPK model is accurately described by either a 2 or 3-exponential function, depending on whether or not there is significant tissue binding. For an accurate estimate of r the first venous sample should be at or before the end of the constant infusion and a long (10 minute) constant infusion is preferable to a bolus injection. For noisy data, a gamma distribution deconvolution provides the best result if the input has the form of a gamma distribution. For other input functions, good results are obtained using deconvolution methods based on modeling the input with either a B-spline or uniform dense set of time points.

Show MeSH