Top

Published in:

01-02-2012 | Brief Article

Dosimetry of ¹⁸F-Labeled Tyrosine Kinase Inhibitor SKI-249380, a Dasatinib-Tracer for PET Imaging

Authors: Mark P. S. Dunphy, Pat Zanzonico, Darren Veach, Romel Somwar, Nagavarakishore Pillarsetty, Jason Lewis, Steven Larson

Published in: Molecular Imaging and Biology | Issue 1/2012

Abstract

Purpose

To obtain estimates of human normal-organ radiation doses of ¹⁸F-SKI-249380, as a prerequisite step towards first-in-human trial. ¹⁸F-SKI-249380 is a first-of-its-kind PET tracer for imaging the in vivo pharmacokinetics of dasatinib, an investigational targeted therapy for solid malignancies.

Procedures

Isoflurane-anesthetized mice received tracer dose via tail vein. Organ time-integrated activity coefficients, fractional urinary and hepatobiliary excretion, and total-body clearance kinetics were derived from PET data, with allometric extrapolation to the Standard Man anatomic model and normal-organ-absorbed dose calculations using OLINDA/EXM software.

Results

The human effective dose was 0.031 mSv/MBq. The critical organ was the upper large intestine, with a dose equivalent of 0.25 mSv/MBq. A 190-MBq administered activity of ¹⁸F-SKI-249380 is thus predicted to expose an adult human to radiation doses generally comparable to those of routinely used diagnostic radiopharmaceuticals.

Conclusions

Animal-based human dose estimates support first-in-human testing of ¹⁸F-SKI-249380.

Available only for authorised users

Luo FR, Barrett Y, Ji P et al (2006) Dasatinib (BMS-354825) pharmacokinetics correlate with pSRC pharmacodynamics in phase I studies of patients with cancer (CA180002, CA180003). J Clin Oncol 24(suppl):3046

U.S. National Institutes of Health (2010). Available at: http://clinicaltrials.gov/. Accessed 11 June 2010.

Demetri GD, Lo Russo P, MacPherson IRJ et al (2009) Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res 15:6232–6240PubMedCrossRef

Wang L, Christopher LJ, Cui D et al (2008) Identification of the human enzymes involved in the oxidative metabolism of dasatinib: an effective approach for determining metabolite formation kinetics. Drug Metab Dispos 36:1828–1839PubMedCrossRef

Veach DR, Namavari M, Pillarsetty N et al (2007) Synthesis and biological evaluation of a fluorine-18 derivative of dasatinib. J Med Chem 50:5853–5857PubMedCrossRef

U.S. Food and Drug Administration (2006). Guidance for industry, investigators, and reviewers: exploratory IND studies.

Stabin MG, Sparks RB, Crowe E (2005) OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 46:1023–1027PubMed

Bolch WE, Eckerman KF, Sgouros G, Thomas SR (2009) MIRD Pamphlet No. 21: a generalized schema for radiopharmaceutical dosimetry—standardization of Nomenclature. J Nucl Med 50:477–484PubMedCrossRef

Cristy M, Eckerman K (1987). Specific absorbed fractions of energy at various ages from internal photons sources. VII. Adult Male. ORNL/TM-8381. Oak Ridge National Laboratory, Oak Ridge, TN

10.

U.S. Food and Drug Administration (2009). 21 CFR Part 361. Prescription drugs for human use generally recognized as safe and effective and not misbranded: drugs used in research

11.

Wang XD, Reeves K, Luo FR, Xu LA, Lee F, Clark E, Huang F (2007) Identification of candidate predictive and surrogate molecular markers for dasatinib in prostate cancer: rationale for patient selection and efficacy monitoring. Genome Biol 8:R255PubMedCrossRef

12.

Peck CC, Cross JT (2007) Getting the dose right: facts, a blueprint, and encouragements. Clin Pharmacol Ther 82:12–14PubMedCrossRef

13.

Workman P, Aboagye EO, Chung YL et al (2006) Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst 98:580–598PubMedCrossRef

14.

Hiwase DK, Saunders V, Hewett D et al (2008) Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 14:3881–3888PubMedCrossRef

15.

Luo FR, Yang Z, Camuso A et al (2006) Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure. Clin Cancer Res 12:7180–7186PubMedCrossRef

16.

Johnson FM, Agrawal S, Burris H et al (2010) Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors. Cancer 116:1582–1591PubMedCrossRef

17.

National Cancer Institute U.S. National Institutes of Health (2002). A workshop regarding what in-vivo molecular imaging probes are needed to support future translational studies in cancer therapeutics. Paper presented at: Strategies for Imaging Priority Targets, Frankfurt, Germany

Title: Dosimetry of 18F-Labeled Tyrosine Kinase Inhibitor SKI-249380, a Dasatinib-Tracer for PET Imaging
Authors: Mark P. S. Dunphy
Pat Zanzonico
Darren Veach
Romel Somwar
Nagavarakishore Pillarsetty
Jason Lewis
Steven Larson
Publication date: 01-02-2012
Publisher: Springer-Verlag
Published in: Molecular Imaging and Biology / Issue 1/2012
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-010-0462-2

At a glance: The STEP trials

Springer Medicine

Dosimetry of ¹⁸F-Labeled Tyrosine Kinase Inhibitor SKI-249380, a Dasatinib-Tracer for PET Imaging

Abstract

Purpose

Procedures

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Labeling Protocols for In Vivo Tracking of Human Skeletal Muscle Cells (HSkMCs) by Magnetic Resonance and Bioluminescence Imaging

Molecular Imaging and Contrast Agent Database (MICAD): Evolution and Progress

The World Molecular Imaging Society (WMIS)

Ex Vivo Imaging of Pancreatic Beta Cells using a Radiolabeled GLP-1 Receptor Agonist

Human Biodistribution and Dosimetry of the PET Radioligand [11C]Flumazenil (FMZ)

Evaluation of 64Cu Labeled GX1: A Phage Display Peptide Probe for PET Imaging of Tumor Vasculature