Safety, biodistribution and radiation dosimetry of [¹²³I]ioflupane in healthy Chinese volunteers

This study sponsored by GE Healthcare (ClinicalTrials.gov identifier: NCT04564092) was conducted according to International Conference on Harmonisation (ICH) Good Clinical Practice Guideline. It was approved by the Ethics committee of the Ruijin hospital. This single-centre study recruited healthy Chinese volunteers. Eligible subjects were generally healthy and fit Chinese males or females aged 18 to 70 years and with a body mass index (BMI) of 18 to 30 kg/m². Pregnant or lactating women were ineligible, and women of childbearing potential had to be willing to use effective contraception. Subjects would be excluded if they had a history of motor disturbances; a history of pulmonary, cardiovascular, renal, hepatic, coagulation, or hormonal disorders, including hyperthyroidism; a history of drug, alcohol, or solvent abuse; use of any investigational medicinal product (IMP) within 30 days prior to screening or receipt of any radionuclide injection within a minimum of 5 radioactive half-lives prior to screening; use of any medication except acetaminophen (paracetamol) or oral contraceptive, including traditional Chinese medications, within 2 weeks of the imaging visit; or classification as a radiation worker.

Subjects were to attend 3 visits: screening, imaging, and follow-up. Medical history, physical examination, clinical laboratory tests and urine analysis, and 12-lead Electrocardiogram (ECG) were obtained for screening and safety assessment purposes. To minimise thyroid uptake of radioactive iodine, subjects had to have appropriate thyroid blocking, according to local practice, prior to and after administration of the IMP.

The primary objective of this phase 1 study was to evaluate the safety of a single dose of [¹²³I]ioflupane injection in Chinese healthy volunteers (HVs). The secondary objectives were: (1) To determine the biodistribution, internal radiation dosimetry, and effective dose (ED) of [¹²³I]ioflupane injection after intravenous (IV) administration in Chinese HVs. (2) To compare biodistribution and dosimetry findings in this Chinese group with those previously established in European HVs. (3) To compare the brain SPECT imaging results in this Chinese group with those previously established in European HVs.

GE Healthcare was responsible for the manufacturing, distribution, and reconciliation of the IMP, [¹²³I]ioflupane injection. The IMP was prepared at GE Healthcare BV, Eindhoven, Netherlands.

Whenever possible, images were acquired at prespecified time points. During the imaging visit, each subject received a single IV bolus injection of [¹²³I]ioflupane with a nominal ¹²³I activity of 111 MBq ± 10% and underwent simultaneous whole-body (head to toe) anterior and posterior planar scintigraphy scans on Intevo 16 SPECT/CT system (Siemens, Erlangen, Germany) at 10 min, 1 h, 2 h, 4 h, 5 h, 24 h, and 48 h after administration. Attenuation correction was performed using transmission scans acquired using a flood source filled with a solution of ¹²³I. Brain SPECT imaging was performed at 3 and 6 h after administration. A reference source was imaged alongside the subject. Whole-body planar images were acquired in a 256 × 1024 matrix and a low-energy, high-resolution, parallel-hole collimator. Brain SPECT acquisition was performed using the same collimator, a 128 × 128 matrix, and a total of 32 frames over 180° with 30 s per frame. After acquisition, Butter-worth low-pass filter and Ramp function were used to reconstruct transverse images.

Blood samples were collected before the [¹²³I]ioflupane injection and at 5, 15, 30 min and 1, 2, 3, 4, 5, 24, and 48 h after injection for pharmacokinetic analysis. For each HV, up to 5-mL venous blood samples were taken at each time point to allow measurement of ¹²³I content in whole blood and plasma over time. The maximum amount of blood taken for activity counting was 55 mL for each HV.

Urine excreted from 1 h before administration of [¹²³I]ioflupane injection to 48 h after injection was collected as voided. The time and volume of each void was recorded. From each void, 3 aliquots of urine of a nominal 1 mL volume each were taken and assayed for ¹²³I activity content over 60 s intervals.

The striatal binding ratio (SBR) is a measure of how much [¹²³I]ioflupane binds to DaT in different regions of the brain compared to a reference region where there is no binding. DaTQUANT™ software was used to automatically delineate the volumes of interest (VOIs) in the striatal regions and reference region (occipital lobe), and quantify left and right SBRs from SPECT images acquired at approximately 3 and 6 h post-injection for each subject. The VOIs of sub-regions over the putamen and caudate were also considered using DaTQUANT™ software. To calculate the SBR, DaTQUANT™ uses a formula that involves dividing the average pixel intensity of a VOI by the average pixel intensity of a reference region (REF). The formula is: SBR = (VOI − REF)/REF.

Time-activity curves were then generated from attenuation corrected, conjugate view ¹²³I activity data for each subject and parameterised by mono- or biexponential curve fitting to calculate the normalised cumulative activity in each source region using the OLINDA/EXM Version 1.1 software [9], which was then used along with the Medical Internal Radiation Dosimetry (MIRD) schema to determine the internal radiation dosimetry [10]. The dosimetry was evaluated for the Cristy–Eckerman female and hermaphrodite male phantoms [11].

Tabulations of summary statistics, graphical presentations, and statistical analyses were performed by using SAS® software, Version 9.4. The last observation prior to administration of IMP was used as the baseline value for calculating post-administration changes from baseline. p-values was interpreted as a metric of uncertainty. Confidence intervals, both individual and simultaneous, were at the 95% confidence level. The 2-sample t-test was used to compare the radiation dosimetry data from the Chinese healthy volunteers (HVs) in this study to the HVs in the earlier European study [8]. The difference between the SBR at 3 and 6 h calculated for each subject was tested by Wilcoxon signed-rank test. No sample size calculation was performed. The sample size was chosen to fulfil regulatory requirements.

The study was initiated on 14 May 2021 and completed on 04 September 2021. All 8 of the enrolled subjects who received [¹²³I]ioflupane completed the study and were included in the pharmacokinetic population.

All subjects were Chinese; the majority were Han Chinese (6 subjects,75%). Four (50%) were male, and 4 (50%) were female. Age ranged from 24 to 41 years, with a median of 29.0 years. Mean height, weight, and body mass index of the subjects were 164.69 cm, 58.18 kg, and 21.099 kg/m², respectively.

All subjects received thyroid blocking medication. All subjects received a dose of [¹²³I]ioflupane in the planned range of 111 MBq ± 10%. The mean (SD) dose of radioactivity injected was 114.6 (5.15) MBq.

Blood sampling was performed for all 8 subjects. Table 1 summarizes the biodistribution of [¹²³I]ioflupane, expressed as the decay-corrected percentage of injected activity in plasma and whole blood. Blood clearance of ¹²³I activity was shown to be rapid. At 5 min after injection, the percentage of injected activity (%IA) present within the blood was 4.564 ± 1.471, falling to 2.220 ± 0.504 at 30 min. The %IA in whole blood was maintained for up to 5 h after injection (1.924 ± 0.403) and showed a gradual reduction to 1.348 ± 0.339 at 24 h and 1.098 ± 0.344 at 48 h after injection. The %IA in plasma was 2.769 ± 0.773 at 5 min, 1.350 ± 0.293 at 30 min, 0.768 ± 0.181 at 24 h, and 0.626 ± 0.138 at 48 h after injection. The %IA values were similar for both whole blood and plasma.

Figure 1 compares the mean whole blood activity curves of [¹²³I]ioflupane in this study (GE001-023) with those obtained during the earlier phase I study (CY 95.FP.1) [8] that enrolled only Europeans (Caucasians). There was no significant difference in decay-corrected %IA in mean whole blood between Chinese and European subjects at any time point.

Figure 2 shows the mean cumulative, decay-corrected and normalised ¹²³I activity excreted in urine for all 8 Chinese subjects where samples were acquired together with the mean curve from the 12 subjects in the European study [8]. Excretion of ¹²³I following the IV administration of ioflupane (¹²³I) injection was determined by measuring the ¹²³I activity within the intestinal contents and the sum of the ¹²³I activities in the voided urine up to 48 h post-injection. During the period of 0 to 5 h after injection, the cumulative mean activity excreted in urine was 8.37 ± 1.73%IA. The mean %IA continued to increase over the period from 5 to 48 h after injection. By 48 h after injection, the mean sum of activity in voided urine was 45.45 ± 8.73% (range: 29.10% to 55.90%) of that injected. If that value is extrapolated for infinite time, the total activity excreted via the renal pathway is 57.40% (range: 31.30% to 89.40%). There was no statistically significant difference in decay-corrected cumulative ¹²³I activity concentration in excreted urine between Chinese and European subjects at time points up to 5 h. A significant difference was seen at 5 to 24 h (p = 0.0204) and 24 to 48 h (p = 0.0029).

Table 2 summarizes the biodistribution in Chinese subjects. The source regions with the highest decay-corrected normalised cumulative activities were remainder (9.409 MBq·h/MBq), lungs (1.664 MBq·h/MBq), and liver (1.255 MBq·h/MBq). Table 3 shows that there was a strong similarity in biodistribution in terms of the decay-corrected normalised cumulative activity between Chinese and European subjects. The 3 source regions with the highest mean normalised cumulative activity were the same in the Chinese HVs and the subjects from the European study, and there was no significant difference between Chinese and European subjects.

Mean SBR in the right striatum was 2.362 at 3 h after injection and 2.558 at 6 h after injection. Mean SBR in the left striatum was 2.376 at 3 h after injection and 2.535 at 6 h after injection. There was no significant difference in SBR at 3 and 6 h post-administration in the striatum, putamen, and caudate (Fig. 3).

Table 4 summarizes radiation dosimetry in Chinese HVs. The effective dose (ED) in the Chinese HVs in this study and the HVs in the earlier European study [8] was compared. The mean ED calculated in this study of Chinese HVs (0.028 ± 0.00448 mSv/MBq) while the sex-averaged ED was 0.027 mSV/MBq (0.025 mSv/MBq male average, 0.032 mSv/MBq female average), this was similar to the value calculated in the study of European HVs (0.023 ± 0.00152 mSv/MBq), the sex-average effective dose determined here is aligned with the published value of 0.025 mSV/MBq for nortropane (FP-CIT) [12].

There was a strong similarity between radiation dosimetry in Chinese and European subjects. The 3 target organs (urinary bladder wall, lower large intestine wall, lungs) with the highest mean absorbed doses as well as the mean absorbed doses in the brain were the same in the Chinese HVs and the European subjects, and there was no significant difference between Chinese and European subjects (Table 5).

Safety analysis included adverse events (AEs), injection-site monitoring, physical examination, vital signs and oxygen saturation, clinical laboratory tests, ECG etc. In this study of Chinese HVs, [¹²³I]ioflupane injection was well tolerated. There were no deaths or other serious adverse events (SAEs), and no AEs led to discontinuation of the study. The majority of AEs were mild in intensity, the most common AEs reported was paraesthesia.

First, this study used standard methods for radiation dosimetry. Differences in the software tools used for modelling residence times could explain small, clinically insignificant differences in dose estimates between the European and Chinese populations. Second, we used the data measured by whole-body planar imaging to calculate initial organ uptake, normalized cumulative activity, absorbed dose, and effective dose. Although the overlap of tissues or organs in planar imaging may make the accuracy of delineating the region of interest limited, planar imaging is still a feasible way to assess the dosimetry of tissues and organs throughout the body.