Abstract
BackgroundIn order to acquire accurate drug pharmacokinetic information, which is required for tissue dosimetry, micro-SPECT must be quantitative to allow for an accurate assessment of radioligand activity in the relevant tissue. This study investigates the feasibility of deriving accurate mouse-specific time-integrated drug pharmacokinetic data in mouse kidneys from activity measurements using micro-SPECT.MethodsAn animal experiment was carried out to evaluate the accuracy of 131I activity quantification in mouse kidneys (mean tissue volume of 0.140 mL) using a micro-SPECT system against conventional ex vivo gamma counting (GC) in a NaI(Tl) detector. The imaging setting investigated was that of the mouse biodistribution of a 131I-labelled single-domain antibody fragment (sdAb), currently being investigated for targeted radionuclide therapy of HER2-expressing cancer. SPECT imaging of 131I 365-keV photons was done with a VECTor/CT system (MILabs, Netherlands) using a high-energy mouse collimator with 1.6-mm-diameter pinholes. For both activity quantification techniques, the pharmacokinetic profile of the radioligand from approximately 1–73 h p.i. was derived and the time-integrated activity coefficient per gram of tissue (ã/M) was estimated. Additionally, SPECT activity recovery coefficients were determined in a phantom setting.ResultsSPECT activities underestimate the reference activities by an amount that is dependent on the 131I activity concentration in the kidney, and thus on the time point of the pharmacokinetic profile. This underestimation is around − 12% at 1.5 h (2.89 MBq mL−1 mean reference activity concentration), − 13% at 6.6 h (149 kBq mL−1), − 40% at 24 h (17.6 kBq mL−1) and − 46% at 73 h (5.2 kBq mL−1) p.i. The ã/M value estimated from SPECT activities is, nevertheless, within − 14% from the reference (GC) ã/M value. Furthermore, better quantitative accuracy (within 2% from GC) in the SPECT ã/M value is achieved when SPECT activities are compensated for partial recovery with a phantom-based recovery coefficient of 0.85.ConclusionThe SPECT imaging system used, together with a robust activity quantification methodology, allows an accurate estimation of time-integrated pharmacokinetic information of the 131I-labelled sdAb in mouse kidneys. This opens the possibility to perform mouse-specific kidney-tissue dosimetry based on pharmacokinetic data acquired in vivo on the same mice used in nephrotoxicity studies.
Highlights
Pharmacokinetic data derived from preclinical studies in in vivo biological models play a key role in the prediction of radiation dosimetry of first-in-human studies of targeted radionuclide therapy
The Single-photon emission computed tomography (SPECT) imaging system used, together with a robust activity quantification methodology, allows an accurate estimation of time-integrated pharmacokinetic information of the 131I-labelled single-domain antibody fragment (sdAb) in mouse kidneys. This opens the possibility to perform mouse-specific kidney-tissue dosimetry based on pharmacokinetic data acquired in vivo on the same mice used in nephrotoxicity studies
The recovery coefficient (RC) of the 4-mm rod decreases by just a few per cent for the lowest concentrations, yet the statistical uncertainty in volume of interest (VOI) activity recovery, uncertainty of activity recovery (URec), significantly increases for concentrations below 0.1 MBq mL−1. Such statistical uncertainty is implicit in the RC values of the 6-mm rod, because they were estimated from just one VOI
Summary
Pharmacokinetic data derived from preclinical studies in in vivo biological models play a key role in the prediction of radiation dosimetry of first-in-human studies of targeted radionuclide therapy. As opposed to GC, microSPECT offers the possibility to quantify radioactivity in tissues in vivo, allowing to derive pharmacokinetic information from one and the same animal. This eliminates the intervariability effects in the assessment of the time dependence of drug pharmacokinetics, since each animal acts as its own control for different sampling time points. In order to acquire accurate drug pharmacokinetic information, which is required for tissue dosimetry, micro-SPECT must be quantitative to allow for an accurate assessment of radioligand activity in the relevant tissue. This study investigates the feasibility of deriving accurate mouse-specific time-integrated drug pharmacokinetic data in mouse kidneys from activity measurements using micro-SPECT
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