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Absorption, distribution and excretion of intravenously injected 68Ge/68Ga generator eluate in healthy rats, and estimation of human radiation dosimetry
EJNMMI Research volume 5, Article number: 40 (2015)
The Erratum to this article has been published in EJNMMI Research 2016 6:51
This study evaluated the absorption, distribution, and excretion of Gallium-68 (68Ga) radionuclide after a single intravenous (i.v.) injection of 68Ge/68Ga generator eluate in healthy rats. Additionally, human radiation doses were estimated from the rat data.
Twenty-one female and 21 male Sprague-Dawley rats were i.v. injected with 47 ± 4 MBq of 68Ge/68Ga generator eluate, and the radioactivity of excised organs was measured using a gamma counter at 5, 30, 60, 120, or 180 min afterwards (n = 3–7 for each time point). The radioactivity concentration and plasma pharmacokinetic parameters were calculated. Subsequently, the estimates for human radiation dosimetry were determined. Additionally, 4 female and 5 male rats were positron emission tomography (PET) imaged for in vivo visualization of biodistribution.
68Ga radioactivity was cleared relatively slowly from blood circulation and excreted into the urine, with some retention in the liver and spleen. Notably, the 68Ga radioactivity in female genital organs, i.e., the uterus and ovaries, was considerable higher compared with male genitals. Extrapolating from the female and male rat 68Ga data, the estimated effective dose was 0.0308 mSv/MBq for a 57-kg woman and 0.0191 mSv/MBq for a 70-kg man.
The estimated human radiation burden of the 68Ge/68Ga generator eluate was slightly higher for females and similar for males as compared with somatostatin receptor ligands 68Ga-DOTANOC, 68Ga-DOTATOC, and 68Ga-DOTATATE, which is probably due to the retention in the liver and spleen. Our results revealed some differences between female and male rat data, which, at least in part, may be explained by the small sample size.
Gallium-68 (68Ga)-labeled tracers are increasingly used in positron emission tomography (PET) for diagnostic purposes. The prototypes of 68Ga-labeled PET imaging agents are the somatostatin receptor ligands, 68Ga-DOTATOC/NOC/TATE peptides, which are today routinely used for PET imaging of neuroendocrine tumors [1–3]. Currently, many other 68Ga-labeled peptide families are under clinical evaluation, such as bombesins (gastrin-releasing peptide receptor ligands), exendins (glucagon-like peptide 1 receptor ligands), and arginine-glycine-aspartic acids (RGDs) (integrin receptor ligands). In addition to oncology, 68Ga-tracer-based PET has been studied for imaging of inflammation .
68Ga offers a cyclotron-independent, convenient, and low-cost access to PET imaging agents. It is readily available by elution from a 68Germanium/68Gallium (68Ge/68Ga) generator possessing a 1-year life span depending on the uploaded 68Ge radioactivity. Furthermore, 68Ga has several convenient characteristics, such as β+ decay 89 %, Eβ+ max 1.9 MeV, and a sufficiently long half-life (67.71 min) for PET imaging.
The purpose of this study was to obtain preclinical information to support the use of the 68Ge/68Ga generator eluate for medical application. The absorption, distribution, and excretion of radioactivity after a single intravenous injection of the 68Ge/68Ga generator eluate were assessed in order to determine the radiation dosimetry of 68Ga. This study investigated the possible consequences of poor radiolabeling efficiency or in vivo dissociation of the radiolabeled conjugate, i.e., issues related to the effects produced in the patient by the free radionuclide. When 68Ga is eluted from 68Ge/68Ga generator with 0.1 mol/l hydrochloric acid solution, it is in the form of 68GaCl3. In aqueous solution; 68Ga is in the form of the hydrated gallium ion [Ga(H2O)6]3+. Insoluble neutral hydroxide colloids 68Ga(OH)3, may precipitated depending on pH (>4) and the concentration of 68Ga. After intravenous injection, the 68Ga radioactivity can migrate in the blood circulation as free 68Ga3+ or 68Ga3+ bound to transferrin, ferritin, or lactoferrin. Here, the absorption, distribution, and excretion of 68Ga radioactivity after a single intravenous (i.v.) injection were studied in healthy, mature Sprague-Dawley rats up to 3 h, and the estimates for human radiation dosimetry were calculated.
All animal experiments were approved by the National Animal Experiment Board in Finland (ELLA) and the Regional State Administrative Agency for Southern Finland (ESAVI) and conducted in accordance with the relevant European Union Directive. This preclinical study was performed without randomization and blinding. The healthy, mature Sprague-Dawley rats were purchased from Harlan, The Netherlands, and they were of specific pathogen free (SPF) quality. The rats were left to acclimate for a minimum of 5 days after their arrival before the study. They were housed at room temperature (18–24 °C) and relative humidity of 40–70 %. Artificial lighting was used, with 12 h of light (6 a.m. to 6 p.m.) and 12 h of dark (6 p.m. to 6 a.m.). The animals received regular feed, and tap water was offered ad libitum. They fasted for 4–6 h prior to the administration of the 68Ge/68Ga generator eluate.
68Ge/68Ga generator eluate
The 68Ge/68Ga generator (Eckert-Ziegler Source No. 1484-7 with 1850 MBq nominal radioactivity at reference date) was eluted with 6 ml of 0.1 mol/l hydrochloric acid; the 0.7−1.2 ml radioactive elution peak was collected and diluted with phosphate-buffered saline (PBS) (600−860 μl, pH 7 ± 0) for i.v. injection.
Twenty-one female (weight 248 ± 13 g) and 21 male rats (weight 342 ± 47 g) were examined at five different time points post-injection (5, 30, 60, 120, and 180 min), with 3–7 female and 3–7 male rats per time point. The animals were placed in an immobilizer (AgnTho’s AB, Lidingö, Sweden), and a catheter was inserted in their tail vein. The rats were i.v. injected with 47 ± 4 MBq of 68Ge/68Ga generator eluate as a bolus and promptly flushed with physiological saline after injection. Animals were killed with an overdose of pentobarbital (Mebunat, Orion Pharma, Finland). Various organs were excised, weighed, and measured for total radioactivity by using a gamma counter (1480 Wizard 3" PerkinElmer/Wallac, Turku, Finland) cross-calibrated with the dose calibrator (VDC-404; Veenstra Instruments, Joure, The Netherlands). Of blood, bone, bone marrow, brown adipose tissue, fat, plasma, skeletal muscle, skin, and urine, only small samples were taken and measured for radioactivity and weight. All other tissues and organs were measured in their entirety. The residual carcass was assessed with a dose calibrator. Urine was obtained directly from the urinary bladder using a needle and syringe, and total radioactivity was measured as described above. Blood was obtained by means of cardiac puncture. Radioactivity of whole blood was measured. Plasma was separated by centrifugation (2118×g for 5 min at 4 °C), and plasma radioactivity was measured. The radioactivity concentration was decay corrected to the time of injection, and the results were expressed as standardized uptake values (SUV) and percentage of injected radioactivity dose per gram of tissue (%ID/g).
In addition to ex vivo studies, nine animals (five males 309–355 g, four females 245–287 g) were PET imaged for 180 min to visualize whole-body distribution in vivo and to obtain time-activity curves. The animals were anesthetized with isoflurane (induction 3 % and maintenance 1.7 %), and a catheter was inserted in their tail vein. The rats were i.v. injected with 45 ± 3 MBq of 68Ge/68Ga generator eluate and imaged by using a High Resolution Research Tomograph (HRRT; Siemens Medical Systems, Knoxville, TN, USA) PET camera. Both rats were imaged at the same time. They were kept on a warm pallet during the imaging procedure. For attenuation correction, a 6-min transmission scan was obtained using a collimated transmission point source. The PET imaging data were reconstructed using the ordered-subsets expectation maximization 3D algorithm (OSEM3D) with attenuation correction based on transmission source measurement.
Plasma pharmacokinetic parameters, i.e., the area under the curve (AUC), elimination rate constant (kel), total clearance (ClT), and half-life (t1/2), were calculated using Microsoft Excel from the plasma concentrations at 5, 30, 60, 120, and 180 min after tracer injection. Only one sample could be obtained from each animal, wherefore the sampled concentrations from all animals (males and females separately) were combined in order to produce the curve of radioactivity concentration vs. time after injection. Since the injected radioactive dose per weight was not exactly the same in all animals, the plasma SUVs (radioactivity concentrations corrected by injected dose and animal weight) were used for calculation. Initial concentration (C 0) was estimated by back-extrapolating from the log-linear regression of the two first concentration values (5- and 30-min samples). AUC between 0 and 180 min was calculated using the linear trapezoidal rule, starting from C 0. Log-linear regression of the last three concentrations (60-, 120-, and 180-min samples) was used to estimate the AUC from 180 min to infinity that is, to calculate AUC0–∞ and to estimate kel and t1/2. Because plasma concentrations were given in SUV units, the total clearance (CIT) is calculated as 1/AUC0–∞, and the unit of CIT is then (g plasma/(g rat × min)).
Estimation of human radiation dose
Absorbed doses were calculated with the OLINDA/EXM version 1.0 software (organ level internal dose assessment and exponential modeling; Vanderbilt University, Nashville, TN, USA), which applies the MIRD schema (developed by the Medical Internal Radiation Dose committee of the Society of Nuclear Medicine) for radiation dose calculations in internal exposure. The software includes radionuclide information and selection of human body phantoms. The residence times derived from the rat data were integrated as the area under the time-activity curve. The residence times were converted into corresponding human values by multiplication with a factor to scale the organ and body weights: (WTB,rat/WOrgan,rat) × (WOrgan,human/WTB,human), where WTB,rat and WTB,human are the body weights of rat and human (a 57-kg female or 70-kg male), respectively; and WOrgan,rat and WOrgan,human are the organ weights of rat and human (organ weights for a 57-kg female or 70-kg male), respectively.
The mean values are calculated from the individual measurements and expressed with an accuracy of one standard deviation (mean ± SD). Differences between genders were assessed with Student’s t test.
Animal and tissue/organ weights and ex vivo biodistribution data from the rats are summarized in Tables 1 and 2, and 180-min results visualized in Fig. 1. 68Ga radioactivity was slowly cleared from blood circulation and excreted predominantly into the urine, with some retention in the liver and kidneys. Interestingly, the 68Ga radioactivity in female genital organs, i.e., the uterus and ovaries, was considerable higher than in male genitals (ovaries 0.750 %ID/g, uterus 0.941, testes 0.198 at 180 min). Plasma had also large difference 2.865 %ID/g (female) vs. 1.544 (male) at 180 min. In vivo PET images were in the line with ex vivo measurements (Fig. 2). Estimated plasma pharmacokinetic parameters for 68Ga radioactivity are given in Table 3. Plasma concentration was relatively high at the final time point (180 min), which may lead in uncertainty in the estimation of AUC0–∞.
The human residence times for the various source organs and radiation dose estimates for 68Ga radioactivity, extrapolated from rat biodistribution data, are listed in Table 4. The estimations of the absorbed doses were calculated for a 70-kg adult male and a 57-kg adult female. Extrapolating from the female rat data, the effective dose for a 57-kg adult female was 0.0308 mSv/MBq, i.e., 7.7 mSv from an intravenously injected radioactivity of 250 MBq. The corresponding estimates for 15-, 10-, 5-, and 1-year-old and newborn females are presented in Table 5. Estimated from female rat data, the absorbed doses were the greatest in heart wall (0.501 mSv/MBq), osteogenic cells (0.076 mSv/MBq), liver (0.072 mSv/MBq), lungs (0.0502 mSv/MBq), and spleen (0.034 mSv/MBq). Extrapolating from the male rat data, the effective dose for a 70-kg adult male was 0.0191 mSv/MBq, i.e., 4.8 mSv from an intravenously injected radioactivity of 250 MBq. The corresponding estimates for 15-, 10-, 5-, and 1-year-old and newborn males are presented in Table 6. Estimated from the male rat data, the absorbed doses were greatest in heart wall (0.216 mSv/MBq), liver (0.0652 mSv/MBq), osteogenic cells (0.0418 mSv/MBq), urinary bladder wall (0.0382 mSv/MBq), and lungs (0.0245 mSv/MBq).
The latest research has produced a series of new compounds labeled with 68Ga, which is a positron-emitting metal especially suitable for labeling of peptides and PET. In this study, we investigated the absorption, distribution, and excretion of 68Ga/68Ge radioactivity after a single intravenous injection of 68Ge/68Ga generator eluate in female and male rats over a period of 3 h.
The observed differences between the female and male biodistribution data are probably, at least in part, due to the small number of animals. However, higher concentrations of some elements, including iron, have been observed in the organs of female rats than in male rats, and since Ga3+ is transported into tissues in a similar way as Fe3+, this may explain part of the gender difference observed in this study . This, in addition to higher injected radioactivity dose per gram, might in part explain higher plasma values of female rats. Interestingly, the estimated human radiation dose was higher when using the female rat data than when using the male rat data. Possible explanations for this include the small sample size and/or actual gender dependent differences in handling certain elements . The body weight of female rats was approximately 100 g lower than that of male rats. However, both genders received an identical 50-MBq dose of 68Ga eluate. This may also be one source of difference.
When the studies started, the 68Ge/68Ga generator was already used for 7 month; the studies lasted up to 5 month. According to manufacturer’s metals screen by inductively coupled plasma mass spectrometry (ICP-MS), the 68Ge/68Ga generator (no. 1484-7, with 1850-MBq nominal radioactivity) had antimony 0.004 ppm, boron 0.17 ppm, sodium 0.56 ppm, titanium 0.069 ppm, and zinc 0.006 ppm, which reflects the typical metal impurities in the eluate. In the respective Ph. Eur. monograph, only zinc and iron are mentioned as metal impurities, because they might interfere as 3+ metals with the Ga-68 during the labeling. The limit of zinc and iron is 10 μg/GBq. The generator has a zinc level of 0.02 μg/GBq, which is well below the limit, and iron was not detected by ICP-MS by a detection limit of 0.006 ppm, which also correlates to a value way below the limit. The 68Ge breakthrough was 0.000017 % correlated to the 68Ga radioactivity of the eluate at the reference date. This value is well below the limit of 68Ge-breakthrough mentioned in the respective Ph. Eur. monograph. Thus, it was estimated that these levels of metal impurities and 68Ge breakthrough had no effect on the results. However, the chemical form of 68Ga used in this study (68Ga eluate was mixed with a phosphate-buffered saline) might be different from 68Ga-species present as by-products in 68Ga-labeled radiopharmaceuticals. In radiolabeling peptides, 68Ga is reacted with chelate-conjugated peptides at elevated temperature, which should accelerate the hydrolysis reaction of Ga that does not form complex with peptide-chelate conjugate.
The whole-body distribution of 68Ga radioactivity reported here is in line with previous publications. Velikyan and co-workers studied biodistribution of 68GaCl3 in healthy Sprague-Dawley rats in order to control the organs where the accumulation would occur in case of impure tracer or in vivo release of 68Ga from the tracer (68Ga-DOTATOC and 68Ga-DOTATATE). The 68GaCl3 was acetate buffered to pH of 4.6 and formulated with phosphate-buffered saline (pH 7.4) for i.v. injection. The 68Ga radioactivity concentration at 75-min post-injection was the highest in the blood, and the accumulation in the heart, lung, liver, and spleen was considerably higher as compared to that of peptide tracers . Previously, we i.v. injected NaOH neutralized 68Ga-chloride (12 MBq from Cyclotron Co. 68Ge/68Ga generator, Obninsk, Russia) in anesthetized, athymic, male Hsd/RH-rnu/rnu rats having subcutaneous tumor xenografts and reported the following SUVs at 90 min after injection (the values at 120 min of the present report are given in the parentheses): blood 2.7 ± 0.3 (3.074 ± 0.337), liver 5.9 ± 3.3 (2.280 ± 0.918), lung 1.9 ± 0.8 (1.445 ± 0.195), muscle 0.2 ± 0.03 (0.478 ± 0.067), and skin 0.5 ± 0.1 (0.662 ± 0.233) . Subsequently, we also studied distribution of 68GaCl3 (Cyclotron Co., Obninsk, Russia) in healthy C57BL/6 N mice. The 68GaCl3 was neutralized with 1 mol/l sodium hydroxide to pH of 7, and the final product contained 13 % of colloidal forms of 68Ga as determined by ultrafiltration. Still, the biodistribution of 68Ga radioactivity was quite similar to the present study. The highest level of 68Ga radioactivity at 3-h post-injection was found in the blood and liver followed by spleen, kidneys, bone with bone marrow, and lung, respectively . Nanni and co-workers have studied 68Ga-citrate in patients with infectious diseases . Since citrate is only a weak chelator of 68Ga, the radionuclide is rapidly released in vivo and subsequently binds to transferrin and some other plasma proteins. The biodistribution of 68Ga-citrate may actually resemble that of free 68Ga or the eluate of the 68Ge/68Ga generator. In clinical whole-body PET scanning, 68Ga-citrate showed relatively high vascular radioactivity, moderate hepatic uptake, mild bone marrow radioactivity, and no bowel radioactivity. The relatively high vascular radioactivity, which is not seen in 67Ga-citrate scintigraphy, was a particularly interesting finding. In the current rat study, the elimination of radioactivity in urine and feces at each time point and the overall mass balance as a percentage of administered radioactivities could not be determined since urine or feces were sampled, not collected in their entirety. The observed high plasma values in rats supports that the 68Ga radioactivity is bound to transferrin.
68Ga has been used extensively for the labeling of synthetic peptides. However, there are only few human dosimetry reports available, including, for example, those on peptide analogues that bind to somatostatin receptors (Table 7) [10–15]. The effective dose of the 68Ge/68Ga generator eluate reported here is somewhat higher than that of 68Ga-DOTANOC and 68Ga-DOTATOC [10, 11]. The higher dose of the 68Ge/68Ga generator eluate can be explained by the slow clearance from the blood and the retention in the liver. The biodistribution of 68Ga-labeled complexes is determined by the pharmacokinetics of the complexing molecules, such as peptides, and not by the incorporated Ga3+.
The radiation dose resulting from the i.v. injection of 68Ga-citrate has been estimated from 67Ga-citrate data . The estimated absorbed dose for total body, calculated assuming a uniform distribution of radioactivity, was 0.052 rads/mCi. For 68Ge/68Ga generator eluate, the total-body radiation dose estimates for female and male rats were 0.02560 and 0.01730 mSv/MBq, respectively. However, the 68Ga-citrate and 68Ga-eluate values are not directly comparable because they are expressed with different units (rads/mCi vs. mSv/MBq), but assuming that only gamma radiation is taken into account for the energy dose, the rad value can be converted into the equivalent dose value rem, thus giving an absorbed dose of 0.052 rem/mCi = 0.014 mSv/MBq. There are limited number of studies comparing the PET tracer dosimetry in animals and humans. Table 8 contains a list of reference studies in which human effective doses derived from preclinical studies are reported and compared to effective doses from human measurements [17–24]. The absorbed doses and effective doses from the in vivo studies in rats may be different from those obtained in human studies because of the dissimilar physiology of rodents and humans. For example, the blood flow rate has a remarkable influence on the time-activity curve shape, the area under the curve, and the measured number of disintegrations.
In this study, scaling between rat and human data was performed using the overall non-organ-specific weight. In general, interspecies extrapolation of biokinetic data is based on the fact that the cellular structures and biochemistry are remarkably alike across the entire animal kingdom. Despite these similarities, however, the extrapolation of biokinetic data from laboratory animals to humans entails uncertainty, particularly for the liver, due to the qualitative differences among various species in the handling of many elements by this organ. Allometric scaling from laboratory animals to humans on the basis of body weight or surface area is the most commonly used method. It is based on the assumption that the biokinetics of compounds primarily depends on the metabolic rate of the animal and that the metabolic rate is a function of the body weight or body surface area of the animal. Yet, several other scaling methods have been proposed , based on, for example, the modeling of pharmacokinetic parameters where the variation of serum protein binding between species is taken into account.
The estimated human radiation burden of the 68Ge/68Ga generator eluate was slightly higher for females and similar for males as compared with somatostatin ligands 68Ga-DOTANOC,68Ga-DOTATOC, and 68Ga-DOTATATE, which is probably due to the retention in the liver and spleen. Our results revealed some differences between female and male rat data, which, at least in part, may be explained by the small sample size.
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The study was conducted within the Finnish Centre of Excellence in Cardiovascular and Metabolic Disease, supported by the Academy of Finland, University of Turku, Turku University Hospital and Åbo Akademi University. This study was sponsored by Eckert & Ziegler Radiopharma GmbH, Berlin, Germany, and further supported by a grant from the Academy of Finland (#258814). Helena Virtanen is a Ph.D. student financially supported by the Drug Research Doctoral Program, University of Turku Graduate School, Finland, and the Finnish Cultural Foundation. Aake Honkaniemi, Jussi Mäkilä and Jouni Tuisku are thanked for their help in PET imaging.
Andrea Schüssele is an employee of Eckert & Ziegler Radiopharma GmbH, Berlin, Germany. The other authors have no competing interests.
HV, HL, TT, AS, MT, and AR contributed to conception and design. AA, HV, TT, HL, VO, TS, RS, and MK contributed to acquisition of data. AA, HV, RS, MK, TT and VO contributed to analysis, and TT, AS, MT, and AR to interpretation of data. AA and HV drafted the manuscript, and TT, HL, VO, TS, RS, MK, AS, MT, and AR were involved with revising it critically for important intellectual content. All authors read and approved the final manuscript.
Anu Autio and Helena Virtanen contributed equally to this work.
An erratum to this article can be found at http://dx.doi.org/10.1186/s13550-016-0205-8.