Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

Joseph J. Grudzinski, John M. Floberg, Sarah R. Mudd, Justin J. Jeffery, Eric T. Peterson, Alice Nomura, Ronald R. Burnette, Wolfgang A. Tome, Jamey P. Weichert, Robert Jeraj

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a slow-clearing agent, 124I-NM404 (n = 10), or a fast-clearing agent, 18F-FLT (3-deoxy-3-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k 12/k 21), central elimination rate constant (k el), and tumor influx-to-efflux ratio (k 34/k 43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using CramerRao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k el(0.009 0.003 h 1), normal body retention, k 12/k 21(0.69 0.16), tumor retention, k 34/k 43(1.44 0.46) and predicted dosimetry, D tumor(3.47 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k el(0.050 0.025 min 1), normal body retention, k 12/k 21 (2.21 0.62) and tumor retention, k 34/k 43(0.65 0.17), and predicted dosimetry, D tumor(0.61 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k 12, and central compartment influx rate constant, k 21, possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C 0, was most sensitive at early time points; central elimination, k el, and tumor efflux, k 43, are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k 12, k 21, k el, k 34and k 43will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

Original languageEnglish (US)
Pages (from-to)1641-1657
Number of pages17
JournalPhysics in Medicine and Biology
Volume57
Issue number6
DOIs
StatePublished - Mar 21 2012
Externally publishedYes

Fingerprint

Radioisotopes
Pharmacokinetics
Neoplasms
Therapeutics
Noise
Appointments and Schedules
Heart Neoplasms
Molecular Imaging
Heterografts

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Grudzinski, J. J., Floberg, J. M., Mudd, S. R., Jeffery, J. J., Peterson, E. T., Nomura, A., ... Jeraj, R. (2012). Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT. Physics in Medicine and Biology, 57(6), 1641-1657. https://doi.org/10.1088/0031-9155/57/6/1641

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT. / Grudzinski, Joseph J.; Floberg, John M.; Mudd, Sarah R.; Jeffery, Justin J.; Peterson, Eric T.; Nomura, Alice; Burnette, Ronald R.; Tome, Wolfgang A.; Weichert, Jamey P.; Jeraj, Robert.

In: Physics in Medicine and Biology, Vol. 57, No. 6, 21.03.2012, p. 1641-1657.

Research output: Contribution to journalArticle

Grudzinski, JJ, Floberg, JM, Mudd, SR, Jeffery, JJ, Peterson, ET, Nomura, A, Burnette, RR, Tome, WA, Weichert, JP & Jeraj, R 2012, 'Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT', Physics in Medicine and Biology, vol. 57, no. 6, pp. 1641-1657. https://doi.org/10.1088/0031-9155/57/6/1641
Grudzinski, Joseph J. ; Floberg, John M. ; Mudd, Sarah R. ; Jeffery, Justin J. ; Peterson, Eric T. ; Nomura, Alice ; Burnette, Ronald R. ; Tome, Wolfgang A. ; Weichert, Jamey P. ; Jeraj, Robert. / Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT. In: Physics in Medicine and Biology. 2012 ; Vol. 57, No. 6. pp. 1641-1657.
@article{008b3497e21a4e7b9a3c61cb28194574,
title = "Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT",
abstract = "We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a slow-clearing agent, 124I-NM404 (n = 10), or a fast-clearing agent, 18F-FLT (3-deoxy-3-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k 12/k 21), central elimination rate constant (k el), and tumor influx-to-efflux ratio (k 34/k 43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using CramerRao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k el(0.009 0.003 h 1), normal body retention, k 12/k 21(0.69 0.16), tumor retention, k 34/k 43(1.44 0.46) and predicted dosimetry, D tumor(3.47 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k el(0.050 0.025 min 1), normal body retention, k 12/k 21 (2.21 0.62) and tumor retention, k 34/k 43(0.65 0.17), and predicted dosimetry, D tumor(0.61 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k 12, and central compartment influx rate constant, k 21, possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C 0, was most sensitive at early time points; central elimination, k el, and tumor efflux, k 43, are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k 12, k 21, k el, k 34and k 43will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.",
author = "Grudzinski, {Joseph J.} and Floberg, {John M.} and Mudd, {Sarah R.} and Jeffery, {Justin J.} and Peterson, {Eric T.} and Alice Nomura and Burnette, {Ronald R.} and Tome, {Wolfgang A.} and Weichert, {Jamey P.} and Robert Jeraj",
year = "2012",
month = "3",
day = "21",
doi = "10.1088/0031-9155/57/6/1641",
language = "English (US)",
volume = "57",
pages = "1641--1657",
journal = "Physics in Medicine and Biology",
issn = "0031-9155",
publisher = "IOP Publishing Ltd.",
number = "6",

}

TY - JOUR

T1 - Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

AU - Grudzinski, Joseph J.

AU - Floberg, John M.

AU - Mudd, Sarah R.

AU - Jeffery, Justin J.

AU - Peterson, Eric T.

AU - Nomura, Alice

AU - Burnette, Ronald R.

AU - Tome, Wolfgang A.

AU - Weichert, Jamey P.

AU - Jeraj, Robert

PY - 2012/3/21

Y1 - 2012/3/21

N2 - We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a slow-clearing agent, 124I-NM404 (n = 10), or a fast-clearing agent, 18F-FLT (3-deoxy-3-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k 12/k 21), central elimination rate constant (k el), and tumor influx-to-efflux ratio (k 34/k 43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using CramerRao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k el(0.009 0.003 h 1), normal body retention, k 12/k 21(0.69 0.16), tumor retention, k 34/k 43(1.44 0.46) and predicted dosimetry, D tumor(3.47 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k el(0.050 0.025 min 1), normal body retention, k 12/k 21 (2.21 0.62) and tumor retention, k 34/k 43(0.65 0.17), and predicted dosimetry, D tumor(0.61 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k 12, and central compartment influx rate constant, k 21, possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C 0, was most sensitive at early time points; central elimination, k el, and tumor efflux, k 43, are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k 12, k 21, k el, k 34and k 43will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

AB - We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a slow-clearing agent, 124I-NM404 (n = 10), or a fast-clearing agent, 18F-FLT (3-deoxy-3-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k 12/k 21), central elimination rate constant (k el), and tumor influx-to-efflux ratio (k 34/k 43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using CramerRao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k el(0.009 0.003 h 1), normal body retention, k 12/k 21(0.69 0.16), tumor retention, k 34/k 43(1.44 0.46) and predicted dosimetry, D tumor(3.47 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k el(0.050 0.025 min 1), normal body retention, k 12/k 21 (2.21 0.62) and tumor retention, k 34/k 43(0.65 0.17), and predicted dosimetry, D tumor(0.61 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k 12, and central compartment influx rate constant, k 21, possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C 0, was most sensitive at early time points; central elimination, k el, and tumor efflux, k 43, are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k 12, k 21, k el, k 34and k 43will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

UR - http://www.scopus.com/inward/record.url?scp=84858019920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858019920&partnerID=8YFLogxK

U2 - 10.1088/0031-9155/57/6/1641

DO - 10.1088/0031-9155/57/6/1641

M3 - Article

VL - 57

SP - 1641

EP - 1657

JO - Physics in Medicine and Biology

JF - Physics in Medicine and Biology

SN - 0031-9155

IS - 6

ER -