Search

Abstract Background Steps have been taken by pharmaceutical companies to obtain marketing authorisation of PSMA ligands in the European Union. Since December 2022, Locametz® (PSMA-11, gozetotide) is licensed as kit for manual radiolabelling with gallium-68 and commercially available since mid-2023. The Summary of Product Characteristic (SmPC) describes manual radiolabelling with a maximum activity after radiolabelling of 1369 MBq. We aimed for radiolabelling with a higher activity to increase production efficiency, and thus, automated radiolabelling is strongly preferred over manual radiolabelling to reduce radiation exposure to personnel. The aim of this study was to develop and validate a method for automated radiolabelling of the Locametz® kit using ~ 2000 MBq of gallium-68 eluate for radiolabelling. Results Automated radiolabelling of [68Ga]Ga-PSMA-11 using the Locametz® kit provided a product which complies to the Ph. Eur., had a shelf-life of 6 h at room temperature, and theoretically reduced radiation exposure 5.7 times. Radiolabelling with one and two generator(s) resulted in a radiochemical yield of 91–102% and 96–101% after preparation, respectively. The radiochemical purity ranged from 98.0 to 99.6% for radiolabelling with one generator and ranged from 98.4 to 99.3% for radiolabelling with two generators with similar stability. The activity of the final product was much higher when using two generators, 1961–2035 MBq compared to 740–1260 MBq, which leads to ~ 1.5 times more patient syringes available per preparation. Conclusion Automated radiolabelling of [68Ga]Ga-PSMA-11 using the Locametz® kit with higher gallium-68 activity than specified in the SmPC results in a product that is in compliance with the Ph. Eur. monograph and has a shelf-life of 6 h at room temperature. Radiolabelling with two generators proved possible and resulted in a product with similar quality but with much higher efficiency.

Abstract Background Automated dispensing systems (ADSs) for radiopharmaceuticals have been developed to reduce the radiation exposure of personnel, to improve the accuracy of the dispensed dose and to limit the microbiological contamination. However, before implementing such systems, validation according to various applicable guidelines is necessary to ensure safety and quality. Here we present the selection, validation and implementation of the PT459R2 from manufacturer Lynax s.r.o. as a guidance protocol for validation according to GMP and GRPP guidelines. Validation included linearity accuracy and precision of the internal scintillation detector for different isotopes and microbiological validation for aseptic procedures. Results The ADS can dispense accurate doses in the following linear range: 1000–10,000 MBq for lutetium-177, 20–74 MBq for zirconium-89, 100–1000 MBq for gallium-68 and 100–2000 MBq for fluorine-18. The maximum bias is 2.35% and the maximum coefficient of variation is 3.03% which meets the acceptance criteria of

Abstract Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main body This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Abstract Studies to evaluate and optimize [177Lu]Lu‐PSMA treatment focus primarily on individual patient data. A population pharmacokinetic (PK) dosimetry model was developed to explore the potential of using imaging data as input for population PK models and to characterize variability in organ and tumor uptake of [177Lu]Lu‐PSMA‐617 in patients with low volume metastatic prostate cancer. Simulations were performed to identify the effect of dose adjustments on absorbed doses in salivary glands and tumors. A six‐compartment population PK model was developed, consisting of blood, salivary gland, kidneys, liver, tumor, and a lumped compartment representing other tissue (compartment 1–6, respectively), based on data from 10 patients who received [177Lu]Lu‐PSMA‐617 (2 cycles, ~ 3 and ~ 6 GBq). Data consisted of radioactivity levels (decay corrected) in blood and tissues (9 blood samples and 5 single photon emission computed tomography/computed tomography scans). Observations in all compartments were adequately captured by individual model predictions. Uptake into salivary glands was saturable with an estimated maximum binding capacity (Bmax) of 40.4 MBq (relative standard error 12.3%) with interindividual variability (IIV) of 59.3% (percent coefficient of variation [CV%]). IIV on other PK parameters was relatively minor. Tumor volume was included as a structural effect on the tumor uptake rate constant (k15), where a two‐fold increase in tumor volume resulted in a 1.63‐fold increase in k15. In addition, interoccasion variability on k15 improved the model fit (43.5% [CV%]). Simulations showed a reduced absorbed dose per unit administered activity for salivary glands after increasing radioactivity dosing from 3 to 6 GBq (0.685 Gy/GBq vs. 0.421 Gy/GBq, respectively). All in all, population PK modeling could help to improve future radioligand therapy research.

Abstract Background Radiopharmaceuticals are considered as regular medicinal products and therefore the same regulations as for non-radioactive medicinal products apply. However, specific aspects should be considered due to the radiochemical properties. Radiopharmaceutical dedicated monographs are developed in the European Pharmacopoeia to address this. Currently, different quality control methods for non-registered radiopharmaceuticals are utilized, often focusing on radio-TLC only, which has its limitations. When the radiochemical yield (RCY) is measured by radio-TLC analysis, degradation products caused by radiolysis are frequently not detected. In contrast, HPLC analysis defines the radiochemical purity (RCP), allowing for detection of peak formation related to radiolysis. During the introduction and optimization phase of therapeutic radiopharmaceuticals, significant percentages of impurities, like radiolysed construct formation, may have consequential impact on patient treatment. Since more hospitals and institutes are offering radiopharmaceutical therapies, such as [177Lu]Lu-PSMA with an in-house production, the demand for adequate quality control is increasing. Here we show the optimization and implementation of a therapeutic radiopharmaceutical, including the comparison of ITLC and HPLC quality control. Results Downscaled conditions (74 MBq/μg) were in concordance to clinical conditions (18 GBq/250 µg, 5 mL syringe/100 mL flacon); all results were consistent with an > 98% RCY (radio-TLC) and stability of > 95% RCP (HPLC). Radio-TLC did not identify radiolysis peaks, while clear identification was performed by HPLC analysis. Decreasing the RCP with 50%, reduced the cell-binding capacity with 27%. Conclusion This research underlines the importance of the radiolabeling and optimization including clinical implementation and clarifies the need for cross-validation of the RCY and RCP for quality control measurements. Only HPLC analysis is suitable for identification of radiolysis. Here we have proven that radiolysed [177Lu]Lu-PSMA has less binding affinity and thus likely will influence treatment efficacy. HPLC analysis is therefore essential to include in at least the validation phase of radiopharmaceutical implementation to ensure clinical treatment quality.

Abstract Background [177Lu]Lu-PSMA is used for the treatment of metastatic castration-resistant prostate cancer. For in-house productions, quality control methods are essential for ensuring product quality, and thus patient safety. During HPLC method development for quality control of [177Lu]Lu-PSMA-I&T, we noticed an unpredictable variability in peak area and height with replicate measurements. After a run, irremovable radioactivity was measured over the whole the length of the HPLC column, with slightly higher activity at the beginning and end of the column. The uniform distribution suggests that [177Lu]Lu-PSMA-I&T interacts with the column. As a result of the interaction, incomplete and variable recovery of injected activity was observed leading to the variability in peak area and height. Therefore the aim of this study was to (1) investigate the effect of sample composition on the interaction of [177Lu]Lu-PSMA-I&T to the HPLC column (measured as recovery, peak area, and peak height), and (2) to compare this with same concentrations of the well-known [177Lu]Lu-PSMA-617. Results Sample composition significantly affects recovery of [177Lu]Lu-PSMA-I&T, leading to a change in peak area and height. Recovery was 24% when diluted with 0.1 mM octreotide, 38% with water, and increased to 95% when diluted with 0.7 mM unlabeled PSMA-I&T. Peak area and height decreased to 26% and 17% when diluted in octreotide and to 41% and 29% when diluted in water, compared to a dilution in PSMA-I&T. Further experiments showed that recovery (and consequently peak area and peak height) reached a plateau of > 99% at concentrations of 0.27 mM and higher. [177Lu]Lu-PSMA-617 also interacts with the HPLC column, leading to lower, but less variable, recovery (9%). The low recovery of [177Lu]Lu-PSMA-617 could not be prevented with addition of unlabeled PSMA-617. Conclusion [177Lu]Lu-PSMA-I&T can undergo an irreversible binding with an HPLC column resulting in a decreased recovery. The recovery is can be highly dependent on sample composition. The addition of a surplus of unlabeled PSMA-I&T leads to an accurate analysis of [177Lu]Lu-PSMA-I&T.

Abstract Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results This commentary of highlights has resulted in 21 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Also the first contribution in relation to MRI-agents is included. Conclusions Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Abstract Background Lymph node dissection is a therapeutic option for prostate cancer patients with a high risk of- or proven lymph node metastases. Radioguided surgery after intravenous injection of [99mTc]Tc-PSMA could improve the selectivity of lymph node dissection. The aim of this project was to develop an automated synthesis method for [99mTc]Tc-PSMA, using the disposables and chemicals used at our institute for [68Ga]Ga-PSMA labeling. Furthermore, quality control procedures and validation results of the automated production of [99mTc]Tc-PSMA conform cGMP and cGRPP are presented. Methods [99mTc]Tc-PSMA is produced fully automatic with a Scintomics synthesis module. Quality control procedures are described and performed for: activity, labeling yield, visual inspection, pH measurement, sterility and endotoxin determination, radionuclide purity, radiochemical purity (99mTc-colloids, unbound [99mTc]pertechnetate, and other impurities), and HEPES content. Three batches of [99mTc]Tc-PSMA were prepared on three separate days for validation and stability testing at 0, 4, 6, and 24 h. Results [99mTc]Tc-PSMA can be successfully manufactured automatically within a [68Ga]Ga-PSMA workflow with the addition of only [99mTc]pertechnetate and stannous chloride. The radiochemical purity after production was highly reproducible (96.3%, 97.6%, and 98.2%) and remained > 90% (required for patient administration) up to 6 h later. Conclusion A fully automated labeling procedure with corresponding quality control methods for production of [99mTc]Tc-PSMA is presented, which is validated according to cGMP and cGRPP guidelines and can be implemented in a GMP environment. The produced [99mTc]Tc-PSMA is stable for up to 6 h. The presented procedure is almost identical to the automated production of [68Ga]Ga-PSMA and can therefore be implemented expediently if a workflow for [68Ga]Ga-PSMA is already in place.

Abstract Monoclonal antibodies (Mabs) have become key drugs in cancer treatment, either as targeted therapies or more recently as immune checkpoint inhibitors (ICIs). The fact that only some patients benefit from these drugs poses the usual question in the field of onco‐hematology: that of the benefit of individual dosing and the potential of therapeutic drug monitoring (TDM) to carry out this individualization. However, Mabs present unique pharmacological characteristics for TDM, and the pharmacokinetic–pharmacodynamic relationship observed should be interpreted differently than that observed for conventional drugs and small molecules. This pharmacology practice review has been summarized from a public debate between the authors at the International TDM and Clinical Toxicology meeting in Banff, 2020, regarding the potential roles of TDM in the Mab/ICI setting.

Abstract Oral administration of docetaxel in combination with the CYP3A4 inhibitor ritonavir is used in clinical trials to improve oral bioavailability of docetaxel. Diarrhea was the most commonly observed and dose‐limiting toxicity. This study combined preclinical and clinical data and investigated incidence, severity and cause of oral docetaxel‐induced diarrhea. In this study, incidence and severity of diarrhea in patients were compared to exposure to orally administered docetaxel. Intestinal toxicity after oral or intraperitoneal administration of docetaxel was further explored in mice lacking Cyp3a and mice lacking both Cyp3a and P‐glycoprotein. In patients, severity of diarrhea increased significantly with an increase in AUC and Cmax (P = .035 and P = .025, respectively), but not with an increase in the orally administered dose (P = .11). Furthermore, incidence of grade 3/4 diarrhea after oral docetaxel administration was similar as reported after intravenous docetaxel administration. Intestinal toxicity in mice was only observed at high systemic exposure to docetaxel and was similar after oral and intraperitoneal administration of docetaxel. In conclusion, our data show that the onset of severe diarrhea after oral administration of docetaxel in humans is similar after oral and intravenous administration of docetaxel and is caused by the concentration of docetaxel in the systemic blood circulation. Mouse experiments confirmed that intestinal toxicity is caused by a high systemic exposure and not by local intestinal exposure. Severe diarrhea in patients after oral docetaxel is reversible and is not related to the route of administration of docetaxel.

Jeroen JMA Hendrikx,1– 3 Jos H Beijnen,1 Alwin DR Huitema1– 3 1Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 2Department of Nuclear Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 3Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The NetherlandsCorrespondence: Jeroen JMA HendrikxDepartment of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1006 BE, The NetherlandsTel +31 205 127 948Email J.Hendrikx@nki.nl With great interest we read the paper by Liao et al in which they compared a 2-weekly bodyweight-based (6 mg/kg) and fixed (480 mg) administration of panitumumab, a monoclonal antibody (Mab) binding the EGFR receptor.1 The authors used a population pharmacokinetics model to simulate pharmacokinetics of 1200 virtual individuals for each strategy. The observed interpatient variability in mean simulated AUC (CVAUCmean) was compared and was 34% (fixed dosing) versus 29% (bodyweight- based dosing). Based on this, the authors concluded for panitumumab that “body weight-based approach is the recommended patient dosing strategy”. View the original paper by Liao and colleagues

As a mediator between lipid metabolism dysfunction, oxidative stress and inflammation, oxidized low-density lipoprotein (oxLDL) is a promising therapeutical target in a wide range of metabolic diseases. In mice, pneumococcal immunization increases anti-phosphorylcholine and oxLDL antibody levels, and reduces atherosclerosis, non-alcoholic steatohepatitis and Niemann–Pick disease burden. These findings suggest that pneumococcal vaccination may be a useful preventive and therapeutical strategy in metabolic disease patients. In this pilot clinical trial, our aim was to determine whether the administration of a pneumococcal vaccine increases anti-phosphorylcholine and anti-oxLDL antibody levels in metabolic disease patients. The following patients were enrolled: four patients with familial partial lipodystrophy (all women, mean age 32 years old); three familial hypercholesterolemia patients (one girl, two boys; mean age 13 years); and two Niemann–Pick type B (NP-B) patients (two men, mean age 37.5 years old). Participants received one active dose of a 13-valent conjugated pneumococcal vaccine (Prevenar 13) and were followed-up for four weeks. Four weeks after Prevenar 13 vaccination, no differences were observed in patients’ levels of anti-oxLDL IgM or IgG antibodies. In addition, we observed a reduction in anti-phosphorylcholine (anti-PC) IgM antibody levels, whereas no differences were observed in anti-PC IgG antibody titers. These findings indicate that Prevenar 13 vaccination does not induce an immune response against oxLDL in patients with metabolic diseases. Therefore, Prevenar 13 is not suited to target the metabolic disruptor and pro-inflammatory mediator oxLDL in patients.