CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS
`Volume 29, Number 7, 2014
`ª Mary Ann Liebert, Inc.
`DOI: 10.1089/cbr.2014.1646
`
`Formulation of Patient Dose of 177Lu-DOTA-TATE
`in Hospital Radiopharmacy in India:
`Preparation Using In Situ Methodology
`Vis-a-Vis Freeze-Dried Kit
`
`Tapas Das and Sharmila Banerjee
`
`Dear Editor:
`
`P eptide receptor radionuclide therapy (PRRT) using radio-
`
`labeled somatostatin analogs, particularly 177Lu-DOTA-
`TATE, is now an established therapeutic modality for the
`treatment of patients suffering from a wide variety of inoperable
`neuroendocrine tumors.1 In the past decade, PRRT has gained
`momentum and at present is being routinely used as a thera-
`peutic regimen in a limited number of countries. In India, PRRT
`employing 177Lu-DOTA-TATE has been in regular use since
`2008, and to date, more than 1000 patient doses have been
`administered in 10 nuclear medicine centers across the country.
`India, with a large population, has a significant number of pa-
`tients who require PRRT, and need to be provided at a rea-
`sonable cost due to the poor affordability in a large part of the
`population. This demands the formulation of the agent using
`177Lu obtained through the more economical and indigenously
`produced direct (n,c) route using enriched 176Lu as a target.2
`However, specific activity of 177Lu produced following this
`route varies significantly from batch to batch due to the variable
`operating conditions of the reactor (scheduled and unscheduled
`shutdowns, power fluctuation, etc.) and variation in irradiation
`cycles used. In addition, variation in logistical factors, such as
`transportation delay, the distance of the hospitals from the ra-
`dionuclide production site, and the date and time of actual ad-
`ministration, contributes to the variation in the specific activity
`of 177Lu available to the end user.
`Therefore, the radiopharmaceutical challenge associated
`with PRRT using 177Lu-DOTA-TATE lies in its preparation
`with adequately high specific activity so that the required
`dose could be deposited in the cancerous lesions without
`saturating the limited number of receptors available on the
`target.3 Since the radiopharmaceutical is prepared at the
`hospital radiopharmacy, the available specific activity of
`177Lu at the time of preparation should be considered for
`formulation of the agent with highest specific activity and
`thus ensuring the maximum therapeutic efficacy. Accord-
`
`ingly, a suitable method for the preparation of patient dose
`of 177Lu-DOTA-TATE has been developed in our labora-
`tory,4 and the methodology has been successfully adopted
`by the nuclear medicine centers in India.2 Preparation of the
`agent following this methodology requires the calculation of
`amount of peptide, radioprotecting agent (gentisic acid), and
`buffer to be used before every single formulation, and these
`vary depending on the specific activity of 177Lu.4 The main
`advantage of this method is that it ensures preparation of the
`agent with maximum possible specific activity.
`The experience of regularly working with various hospitals
`made us realize that the success of this method largely de-
`pends on the working personnel
`in the respective radio-
`pharmacies, as this procedure requires careful adjustment of
`certain critical reaction parameters. Particularly, adjustment of
`pH of the highly radioactive reaction mixture before incuba-
`tion is very crucial and challenging for obtaining the agent
`with adequately high radiochemical purity. Consequently,
`there is an increased possibility of radioactive contamination
`of the workplace as well as radiation exposure to the working
`personnel. Moreover, a small deviation from the standard
`procedure or error in calculation may lead to batch failure and
`consequently loss of expensive peptide and radioactivity. This,
`in turn, sometimes adversely affects the treatment schedule of
`the patients. Additionally, stringent fulfillment of certain other
`parameters, such as facility to prepare in an environmentally
`controlled atmosphere, utilization of high-quality chemicals,
`and use of pyrogen-free and autoclaved glasswares, is essen-
`tial for the successful implementation of this methodology in
`the hospital radiopharmacy units. Finally,
`the preparation
`Ò
`filtration before it
`needs to be made sterile through Millipore
`can be administered in patients. The whole procedure should
`be accomplished according with the principles and require-
`ments of Good Manufacturing Practice as developed by
`World Health Organization.5
`On the other hand, clinical grade 177Lu-DOTA-TATE
`could also be prepared at the hospital radiopharmacy using
`
`Radiopharmaceuticals Chemistry Section, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre, Trombay, Mumbai,
`India.
`
`Address correspondence to: Tapas Das; Radiopharmaceuticals Chemistry Section, Radiochemistry and Isotope Group; RLG Building,
`Mumbai 400085, Maharashtra, India
`E-mail: tdas@barc.gov.in
`
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`DAS AND BANERJEE
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`freeze-dried DOTA-TATE kits.6,7 Toward this, the authors
`have reported the detailed formulation and radiochemical
`evaluation of a novel freeze-dried DOTA-TATE kit, which
`can be used for the preparation of up to 7.4 GBq of 177Lu-
`DOTA-TATE.8 This single-vial kit, which enables a conve-
`nient and single-step preparation of the agent using 177Lu
`having specific activity of ‡ 740 MBq/lg, is presently being
`used for the treatment of patients in a couple of nuclear
`medicine centers in India.7 As the preparation of the agent
`using the kit requires only the addition of water and 177LuCl3
`before incubation, the formulation is relatively simple at the
`end user. This also reduces the possibility of contamination,
`radiation exposure, batch failure, and the preparation time of
`the radiopharmaceutical. However, this methodology has the
`drawback of using a fixed amount of DOTA-TATE, and thus,
`the preparation may contain more DOTA-TATE than re-
`quired, particularly when 177Lu of higher specific activity is
`used for the preparation.
`Both the methods, with respective merits and limitations,
`have been proven to be useful in preparing patient dose
`of 177Lu-DOTA-TATE with adequately high radiochemi-
`cal purity. In consideration, it is advantageous to follow the
`in situ preparation methodology in centers having a well-
`equipped radiopharmacy and well-trained radiochemists as
`it always ensures the formulation of 177Lu-DOTA-TATE
`with highest possible specific activity. On the other hand,
`the use of the freeze-dried kit may be a more desirable
`option in other centers to make PRRT an accessible thera-
`peutic modality to a large number of patients.
`
`References
`
`1. Dong C, Liu Z, Wang F. Peptide-based radiopharmaceuticals
`for targeted tumor therapy. Curr Med Chem 2014;21:139.
`2. Das T, Pillai MRA. Options to meet the future global de-
`mand of radionuclides for radionuclide therapy. Nucl Med
`Biol 2013;40:23.
`3. Breeman WAP, de Jong M, Visser TJ, et al. Optimising
`conditions for radiolabelling of DOTA-peptides with 90Y,
`111In and 177Lu at high specific activities. Eur J Nucl Med
`Mol Imaging 2003;30:917.
`4. Das T, Chakraborty S, Kallur KG, et al. Preparation of pa-
`tient doses of 177Lu-DOTA-TATE using indigenously produced
`177Lu: The Indian experience. Cancer Biother Radiopharm
`2011;26:395.
`5. World Health Organization. Guidelines on Good Manu-
`facturing Practices for radiopharmaceutical products, Annex 3.
`WHO Technical Report Series, No. 908, 2003.
`6. Kwekkeboom DJ, Bakker WH, Kooij PPM, et al. [177Lu-
`DOTA0,Tyr3]octreotate: Comparison with [111In-DTPA0]octre-
`otide in patients. Eur J Nucl Med Mol Imaging 2001;28:1319.
`7. Kunikowska J, Krolicki L, Hubalewska-Dydejczyk A, et al.
`Clinical results of radionuclide therapy of neuroendocrine
`tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DO-
`TATATE: Which is a better therapy option? Eur J Nucl Med
`Mol Imaging 2011;38:1788.
`8. Das T, Bhadwal M, Banerjee S, et al. Preparation of DOTA-
`TATE and DOTA-NOC freeze-dried kits for formulation of
`patient doses of 177Lu-labeled agents and their comparison
`for peptide receptor radionuclide therapy application. J
`Radioanal Nucl Chem 2014;299:1389.
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