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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 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.

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.

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"Binding" PBPK model with exact data sampled at high resolution using 3-exponential response function. Same as figure 4 except that a 3-exponential bolus response function was used.
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Figure 6: "Binding" PBPK model with exact data sampled at high resolution using 3-exponential response function. Same as figure 4 except that a 3-exponential bolus response function was used.

Mentions: "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.


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 high resolution using 3-exponential response function. Same as figure 4 except that a 3-exponential bolus response function was used.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: "Binding" PBPK model with exact data sampled at high resolution using 3-exponential response function. Same as figure 4 except that a 3-exponential bolus response function was used.
Mentions: "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.

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 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.

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
Related in: MedlinePlus