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Introduction Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. Methods From 49 pediatric patients (0.7–17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. Results A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5–57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32–2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9–50.3 mg/L*h) on day 1. Conclusion Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules.

Introduction Rhenium-188-HEDP (188Re-HEDP) is a therapeutic radiopharmaceutical for treatment of osteoblastic bone metastases. No standard procedure for the preparation of this radiopharmaceutical is available. Preparation conditions may influence the quality and in vivo behaviour of this product. In this study we investigate the effect of critical process parameters on product quality and stability of 188Re-HEDP. Methods A stepwise approach was used, based on the quality by design (QbD) concept of the ICH Q8 (Pharmaceutical Development) guideline. Potential critical process conditions were identified. Variables tested were the elution volume, the freshness of the eluate, the reaction temperature and time, and the stability of the product upon dilution and storage. The impact of each variable on radiochemical purity was investigated. The acceptable ranges were established by boundary testing. Results With 2 ml eluate, adequate radiochemical purity and stability were found. Nine ml eluate yielded a product that was less stable. Using eluate stored for 24 h resulted in acceptable radiochemical purity. Complexation for 30 min at room temperature, at 60 °C and at 100 °C generated appropriate and stable products. A complexation time of 10 min at 90 °C was too short, whereas heating 60 min resulted in products that passed quality control and were stable. Diluting the end product and storage at 32.5 °C resulted in notable decomposition. Conclusion Two boundary tests, an elution volume of 9 ml and a heating time of 10 min, yielded products of inadequate quality or stability. The product was found to be instable after dilution or when stored above room temperature. Our findings show that our previously developed preparation method falls well within the proven acceptable ranges. Applying QbD principles is feasible and worthwhile for the small-scale preparation of radiopharmaceuticals.

Item does not contain fulltext In patients with metastatic castration-resistant prostate cancer, bone is the most common site for metastases. Because of their osteoblastic character, these lesions are very suitable for treatment with bone-seeking radiopharmaceuticals (RPs). Nowadays, radium-223-chloride is the only RP with a proven benefit in overall survival, whereas the beta-emitting RPs are used for pain palliation. In the past, many trials that investigated RPs alone, or in combination with chemotherapy have been performed. Because of different designs, characteristics of included patients, and chemotherapeutical and RP regimens, interpretation of the promising data and positioning of RPs in the treatment of metastatic prostate cancer has become difficult. In this review, we provide an overview of the existing data per RP with a focus on the different RPs in combination with chemotherapy. Furthermore, we aim to clarify the benefits on pain response and quality of life. Finally, we focus on the optimal timing and use of biomarkers in the treatment of patients with castration-resistant prostate cancer with RPs.

Contains fulltext : 154378.pdf (Publisher’s version ) (Closed access) Radiopharmaceuticals are highly regulated, because they are controlled both as regular medicinal products and as radioactive substances. This can pose a hurdle for their development and clinical use. Radiopharmaceuticals are fundamentally different from other medicinal products and these regulations are not always adequate for their production. Strict compliance may have a huge resource impact, without further improving product quality. In this paper we give an overview of the applicable legislation and guidelines and propose a risk-based approach for their implementation. We focus on a few controversial Good Manufacturing Practice topics: cleanroom classification, air pressure regime, cleanroom qualification and microbiological monitoring. We have developed an algorithm to assess the combined risk of microbiological contamination of a radiopharmaceutical preparation process and propose corresponding Good Manufacturing Practice classification levels. In our opinion, the risk of carry-over of radiopharmaceuticals by individuals cannot be contained by pressure differences, and complicated regimes with underpressured rooms are not necessary in most situations. We propose a sterility assurance level of 10 for radiopharmaceuticals that are administered within a working day, irrespective of their use. We suggest the adoption of limits for environmental monitoring of microbial contamination, as proposed by Bruel and colleagues, on behalf of the French Society of Radiopharmacy. Recently launched regulatory documents seem to breathe a more liberal spirit than current legislation and recognize the need for the use of risk assessment. We argue that future legislation be further harmonized and state risk assessment as the gold standard for implementation of drug quality regulations for the preparation of unlicensed radiopharmaceuticals.

Item does not contain fulltext INTRODUCTION: (188)Rhenium-HEDP is an effective bone-targeting therapeutic radiopharmaceutical, for treatment of osteoblastic bone metastases. It is known that the presence of carrier (non-radioactive rhenium as ammonium perrhenate) in the reaction mixture during labeling is a prerequisite for adequate bone affinity, but little is known about the optimal carrier concentration. METHODS: We investigated the influence of carrier concentration in the formulation on the radiochemical purity, in-vitro hydroxyapatite affinity and the in-vivo bone accumulation of (188)Rhenium-HEDP in mice. RESULTS: The carrier concentration influenced hydroxyapatite binding in-vitro as well as bone accumulation in-vivo. Variation in hydroxyapatite binding with various carrier concentrations seemed to be mainly driven by variation in radiochemical purity. The in-vivo bone accumulation appeared to be more complex: satisfactory radiochemical purity and hydroxyapatite affinity did not necessarily predict acceptable bio-distribution of (188)Rhenium-HEDP. CONCLUSIONS: For development of new bisphosphonate-based radiopharmaceuticals for clinical use, human administration should not be performed without previous animal bio-distribution experiments. Furthermore, our clinical formulation of (188)Rhenium-HEDP, containing 10 mumol carrier, showed excellent bone accumulation that was comparable to other bisphosphonate-based radiopharmaceuticals, with no apparent uptake in other organs. ADVANCES IN KNOWLEDGE: Radiochemical purity and in-vitro hydroxyapatite binding are not necessarily predictive of bone accumulation of (188)Rhenium-HEDP in-vivo. IMPLICATIONS FOR PATIENT CARE: The formulation for (188)Rhenium-HEDP as developed by us for clinical use exhibits excellent bone uptake and variation in carrier concentration during preparation of this radiopharmaceutical should be avoided.

Background: For patients with castration-resistant prostate cancer (CRPC) metastatic to bone, treatment with bone seeking radiopharmaceuticals is an important treatment option, both for pain palliation and improvement of survival. Radium-223-chloride (an alpha-emitter) has a proven survival benefit. Some small clinical studies suggest that rhenium-188-HEDP, a beta-emitter that is well-known for its effect on pain palliation, may have a beneficial effect on survival as well. A major advantage of rhenium-188-HEDP, compared to radium-223-chloride is the production on-site at a healthcare institute, resulting in rapidly availability and lower costs. Other advantages of rhenium-188-HEDP includes more favorable physical characteristics (shorter half-life and longer penetration depth) and being more patient-friendly (3 instead of 6 administrations) compared to radium-223-chloride. Despite some promising data in small randomized studies, the potential effect on patient survival of rhenium-188-HEDP needs to be established in a randomized phase III study. Methods: The RaRe trial is a multicenter, randomized, open-label, controlled phase III study comparing the efficacy of repeated treatment with radium-223-chloride and repeated treatment with rhenium-188-HEDP in patients with CRPC metastatic to bone. The aim of the trial is to include 402 participants who are randomized to one of the two treatment groups in a 1:1 ratio. The primary endpoint is overall survival (OS), and the secondary endpoints are pain response, quality of life (QoL), time to first occurrence of skeletal related event (SRE), prostate specific antigen (PSA) progression, total alkaline phosphatase (tALP) progression, and incremental cost-effectiveness. An interim analysis for futility will be performed after the inclusion of 90 patients in each treatment group. Discussion: In this randomized phase III trial we hypothesize that treatment with rhenium-188-HEDP results in an improved survival in patients with CRPC metastatic to bone as compared to the current standard treatment with radium-223-chloride. We also expect to demonstrate that treatment with rhenium-188-HEDP improves pain response and quality of life of CRPC patients. Results coming from this study may help to find a better treatment for CRPC patients, while reducing costs. In current times of exponential growth of healthcare costs, we believe that this study is meaningful from the perspective of cost-effectiveness. Clinicaltrials.gov identifier: NCT03458559. Registered 8 March 2018. Trial status: recruiting. Citation Format: Jessica C. Notohardjo, Esther W. Bouman-Wammes, Joyce M. van Dodewaard - de Jong, Haiko J. Bloemendal, Rogier Lange, Rob ter Heine, Henk M. Verheul, John M. de Klerk, Alfons J. van den Eertwegh. Repeated radium-223-chloride versus rhenium-188-HEDP in patients with metastatic castration-resistant prostate cancer: RaRe study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT145.

Objective: Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the β-radiation emitted by 188Re might be enhanced by combination with chemotherapy, using the radiosensitization concept. Therefore, the authors investigated the combined treatment of the taxanes, docetaxel and cabazitaxel, with 188Re in prostate carcinoma cell lines. Materials and Methods: The cytotoxic effects of single and combined treatment with taxanes and 188Re were investigated in three human prostate carcinoma cell lines (PC-3, DU 145, and LNCaP), using the colony-forming assay. The half maximal effective concentration (EC50) of all individual agents was determined. The combined treatment was studied at 0.25, 0.5, 1, 2, and 4 times the EC50 of each agent. The interaction was investigated with a regression model. Results: The survival curves showed dose-dependent cell growth inhibition for both the taxanes and 188Re. The regression model showed a good capability of explaining the data. It proved additivity in all combination experiments and confirmed a general trend to a slight subadditive effect. Conclusions: This proof-of-mechanism study exploring radiosensitization by combining 188Re and taxanes showed no synergism, but significant additivity. This encourages the design of in vivo studies. Future research should explore the potential added value of concomitant treatment of bone metastases with chemotherapy and 188Re-HEDP.

Item does not contain fulltext Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents.

Summary Aim: Rhenium-188-HEDP (188Re-HEDP) is an effective radiopharmaceutical for the palliative treatment of osteoblastic bone metastases. However, only limited data on its routine use are available and its effect on quality of life (QoL) has not been studied. Therefore, we evaluated the clinical benefit of 188Re-HEDP in routine clinical care. Patients and methods: Prostate or breast cancer patients with painful bone metastases receiving 188Re-HEDP as a routine clinical procedure were eligible for evaluation. Clinical benefit was assessed in terms of efficacy and toxicity. Pain palliation and QoL were monitored using the visual analogue scale (VAS), corrected for opioid intake, and the EORTC QLQ-C30 Global health status/QoL-scale. Thrombocyte and leukocyte nadirs were used to assess haematological toxicity. Results: 45 and 47 patients were evaluable for pain palliation and QoL, respectively. After a single injection of 188Re-HEDP, the overall pain response rate was 69% and mean VAS-scores decreased relevantly and significantly (p < 0.05). Repeated treatment resulted in similar pain response. The overall QoL response rate was 68% and mean Global health status/QoL-scores increased relevantly and significantly. Haematological side effects were mild and transient. Conclusion: The clinically relevant response on pain and quality of life and the limited adverse events prove clinical benefit of treatment with 188Re-HEDP and support its use in routine clinical care. Its effectiveness appears comparable to that of external beam radiotherapy.

The quality of pharmaceutical preparations is the result of the design and the execution of the manufacturing process. The Good Manufacturing Practice (GMP) principles and guidelines are about incorporating quality into all aspects of the manufacturing process. This chapter covers the design, execution, monitoring and validation of the process, as well as the quality control and release of the product.

Aims In order to avoid the potential for elevated serum lipid levels as a consequence of long term sedation with propofol, a formulation of propofol 6% in Lipofundin® MCT/LCT 10% (Propofol 6% SAZN) has been developed. The pharmacokinetics, induction of anaesthesia and safety characteristics of this new formulation were investigated after bolus injection and were compared with the commercially available product (propofol 1% in Intralipid® 10%, Diprivan®-10) and propofol 1% in Lipofundin® MCT/LCT 10% (Propofol 1% SAZN). Methods In a randomised double-blind study, 24 unpremedicated female patients received an induction dose of propofol of 2.5 mg kg−1 over 60 s which was followed by standardized balanced anaesthesia. The patients were randomized to receive propofol as Propofol 6% SAZN, Propofol 1% SAZN or Diprivan®-10. Results For all formulations the pharmacokinetics were adequately described by a tri-exponential equation, as the propofol concentrations collected early after the injection suggested an additional initial more rapid phase. The average values for clearance (CL), volume of distribution at steady-state (Vd,ss ), elimination half-life (t1/2,z ) and distribution half-life (t1/2,λ2) observed in the three groups were 32±1.5 ml kg−1 min−1, 2.0±0.18 l kg−1, 95±5.6 min and 3.4±0.20 min, respectively (mean±s.e.mean, n=24) and no significant differences were noted between the three formulations (P >0.05). The half-life of the additional initial distribution phase (t1/2,λ1 ) in all subjects ranged from 0.1 to 0.6 min. Anaesthesia was induced successfully and uneventfully in all cases, and the quality of induction was adequate in all 24 patients. The induction time did not vary between the three formulations and the average induction time observed in the three groups was 51±1.3 s which corresponded to an induction dose of propofol of 2.1±0.06 mg kg−1 (mean±s.e.mean, n=24). The percentage of patients reporting any pain on injection did not vary between the formulations and was 17% for the three groups. No postoperative phlebitis or other venous sequelae of the vein used for injection occurred in any of the patients at recovery of anaesthesia nor after 24 h. Conclusions From the above results, we conclude that the alteration of the type of emulsion and the higher concentration of propofol in the new parenteral formulation of propofol does not affect the pharmacokinetics and induction characteristics of propofol, compared with the currently available product. Propofol 6% SAZN can be administered safely and has the advantage of a reduction of the load of fat and emulsifier which may be preferable when long term administration of propofol is required.

Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint.

Bone-targeting therapeutic radiopharmaceuticals are effective agents for treatment of painful bone metastases. Rhenium-188-HEDP is such a therapeutic radiopharmaceutical and has advantages over commercially available alternatives in terms of efficacy, safety and the ability to be produced on-site, allowing rapid treatment upon presentation of patients with pain. Unlike many other radiopharmaceuticals, there are no standardized preparation methods for Rhenium-188-HEDP. It is known, however, that drug composition may not only affect stability of the final drug product, but it may also influence bone affinity and, thus, efficacy. Furthermore, for support of clinical studies with Rhenium-188-HEDP as an investigational medicinal product, preparation of this radiopharmaceutical has to be performed under GMP conditions. To our knowledge, no group has reported on the preparation of Rhenium-188-HEDP under GMP conditions or on stock production of sterile non-radioactive starting materials. We present the production of GMP grade Rhenium-188-HEDP for application of this therapeutic radiopharmaceutical in routine clinical practice and for support of clinical studies. In addition, bio-distribution data of Rhenium-188-HEDP in mice and in patients with bone metastases originating from prostate cancer are presented.