Preparation of Patient Doses of 177 Lu-DOTA-TATE Using Indigenously Produced 177 Lu: The Indian Experience

Abstract

Purpose:

¹⁷⁷Lu (T _1/2 = 6.73 days, E _β(max) = 0.497 MeV, E _γ = 113 KeV [6.4%] and 208 KeV [11%])-labeled DOTA-TATE, a somatostatin analog, is presently being considered a promising agent for the treatment of patients suffering from inoperable neuroendocrine tumors, which overexpress somatostatin receptors. The objective of the present work was to develop an optimized protocol for the preparation of therapeutic dose of ¹⁷⁷Lu-DOTA-TATE with as high as achievable specific activity at the time of its administration, taking into account the variable specific activity of ¹⁷⁷Lu available during the preparation of the agent.

Methods:

¹⁷⁷Lu labeling of DOTA-TATE was carried out using a precalculated amount of DOTA-TATE based on the available specific activity of ¹⁷⁷Lu at the time of preparation, keeping a minimum molar ratio of [DOTA-TATE]:[Lu] = 4:1, so that ¹⁷⁷Lu-DOTA-TATE could be obtained with highest possible specific activity without compromising its radiochemical purity and stability.

Results:

One hundred (100) batches of ¹⁷⁷Lu-DOTA-TATE were prepared following this protocol till date at five different nuclear medicine centers of India, with a radiochemical purity of 98.25% ± 1.1% and specific activity of 32.74–65.49 GBq/μmol (885–1770 mCi/μmol). Till date, 250 patient doses of ¹⁷⁷Lu-DOTA-TATE have been dispensed and administered in 150 patients suffering from various types of neuroendocrine-originated tumors.

Conclusions:

The developed method ensures that patient doses of ¹⁷⁷Lu-DOTA-TATE could be prepared with highest possible specific activity depending upon the available specific activity of ¹⁷⁷Lu at the hospital radiopharmacy.

Introduction

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs is a novel therapeutic modality for patients with somatostatin receptor-positive tumors. [DOTA⁰,Tyr³]octreotate (DOTA-TATE) labeled with ¹⁷⁷Lu [T _1/2 = 6.73 days, E _β(max) = 0.497 MeV, E _γ = 113 KeV (6.4%) and 208 KeV (11%)] has emerged as a promising agent for the treatment of patients suffering from inoperable neuroendocrine-originated tumors.^1

–7 One of the challenges involved in carrying out targeted tumor therapy using ¹⁷⁷Lu-DOTA-TATE, like any other receptor-specific radiotherapeutic agent, is to prepare the radiolabeled conjugate with adequately high specific activity in order that sufficient activity can be deposited in the cancerous lesions without saturating the limited number of receptors present in the cancerous site.^8
–10 Although no-carrier-added (nca) ¹⁷⁷Lu produced by indirect route involving the neutron irradiation of enriched (in ¹⁷⁶Yb) Yb₂O₃ target followed by β⁻ particle emission is ideally suited for obtaining radiolabeled conjugates in very high specific activity, the difficulty involved in the separation of two adjacent members of lanthanides is a major practical drawback. It has been already documented that ¹⁷⁷Lu could be produced with adequate specific activity for preparing receptor-specific radioconjugates by direct neutron activation of enriched ¹⁷⁶Lu target.^10
–12 However, the specific activity of ¹⁷⁷Lu produced by thermal neutron activation of ¹⁷⁶Lu available at the hospital radiopharmacy may vary considerably depending on various irradiation parameters, namely, thermal neutron flux, duration of irradiation, power fluctuation, intermediate shutdowns, and also ¹⁷⁶Lu enrichment in the target. Another important aspect is the wide range of time required to deliver the radionuclide to the nuclear medicine centers. This is a very important consideration, especially in vast countries such as India, where a large number of nuclear medicine clinics need to be catered using limited radionuclide production facility. As the specific activity of ¹⁷⁷Lu available at the time of preparation of the agent may vary considerably, the optimization of the labeling protocol with respect to the amount of peptide, in order that it can be prepared with high radiochemical purity using minimum amount of DOTA-TATE, is very crucial and poses a challenge to the hospital radiopharmacy technicians preparing the therapeutic doses of ¹⁷⁷Lu-DOTA-TATE for administration to the patients. On the other hand, the use of lyophilized kits of DOTA-TATE with a fixed amount of conjugate would only work within a well-defined range of specific activity.

The present study describes the optimization of the radiolabeling protocol for the preparation of ¹⁷⁷Lu-DOTA-TATE at the hospital radiopharmacy for clinical application in human patients using indigenously produced ¹⁷⁷Lu. Rapid and convenient quality control techniques have also been developed to ascertain the suitability of the preparation before human administration. One hundred (100) batches of ¹⁷⁷Lu-DOTA-TATE have been prepared using the protocol developed and 250 patient doses have been administered till date at various nuclear medicine centers located in different parts of India with encouraging results.

Materials and Methods

Lutetium oxide (64.3%, 74%, and 82% enriched in ¹⁷⁶Lu, spectroscopic grade, >99.99% pure) was obtained from Trace Sciences International, Inc. DOTA-TATE was purchased from PiChem. Gentisic acid (2,5-dihydroxybenzoic acid) was obtained from Aldrich Chemical Company. All other chemicals and solvents used were of AR grade and supplied by reputed local chemical manufacturers. Radionuclidic purity of ¹⁷⁷Lu was ascertained by high-resolution gamma ray spectrometry using an HPGe detector (EGG Ortec/Canberra detector) coupled to a 4K multichannel analyzer (MCA) system after radiochemical processing. All other radioactivity measurements were carried out using well-type NaI(Tl) scintillation counter (Electronic Corporation of India Limited) after adjusting the baseline at 150 keV and keeping a window of 100 keV, thereby utilizing the 208 keV gamma photon of ¹⁷⁷Lu. Paper chromatography (PC) strips were purchased from Whatman. The high-performance liquid chromatography (HPLC) system (PU 1580) was obtained from Jasco. The elution was monitored by detecting the radioactivity signal using a well-type NaI(Tl) detector coupled with the HPLC system. All the solvents used for HPLC were degassed and filtered prior to use and were of HPLC grade.

Production of ¹⁷⁷Lu

¹⁷⁷Lu was produced by thermal neutron bombardment on enriched Lu₂O₃ targets (64.3%, 74%, and 82% in ¹⁷⁶Lu) at a neutron flux ranging from 6 × 10¹³ to 1 × 10¹⁴ n/(cm²s) for 21 days at the DHRUVA reactor of Bhabha Atomic Research Centre. The target was subsequently cooled for 24 hours to eliminate the possibility of the presence of ^176mLu (T _1/2 = 3.7 hours) as radionuclidic impurity. Radiochemical processing was performed by dissolving the irradiated target in 2 N HCl by gentle warming inside a lead-shielded plant. The resultant solution was evaporated to near-dryness and reconstituted in double-distilled water. The evaporation and reconstitution step was repeated 2–3 times. The amount of ¹⁷⁷Lu activity produced and radionuclidic purity of the produced ¹⁷⁷Lu were determined following the procedures reported in the literature.^10,11

Calculation for arriving at the optimal protocol for a patient dose

For the preparation of a patient dose of ¹⁷⁷Lu-DOTA-TATE with the highest possible specific activity at the time of administration to the patients, it is necessary to calculate the exact amount/volume of each component required for every batch. To achieve this, first the volume of ¹⁷⁷LuCl₃ required to prepare a particular patient dose (say, 7.40 GBq [200 mCi]) was calculated from the known radioactive concentration of ¹⁷⁷LuCl₃ after the necessary decay correction. To determine the minimum amount of DOTA-TATE, which will be required to prepare ¹⁷⁷Lu-DOTA-TATE with adequate stability postpreparation, it is necessary to ascertain the amount of Lu that will be present in the preparation to yield the required dose. This can be calculated from the known specific activity of ¹⁷⁷Lu, taking into account the necessary decay correction. The requirement of DOTA-TATE was subsequently determined considering DOTA-TATE:Lu molar ratio to be 4:1. In earlier studies, it was observed that to obtain ¹⁷⁷Lu-DOTA-TATE with adequately high radiochemical purity, maintaining a minimum molar ratio of [DOTA-TATE]:[Lu] = 4:1 is absolutely necessary.¹⁰ Finally, the required volume of 0.1 M ammonium acetate buffer (pH ∼5) was calculated by considering that its volume should be three times the volume equivalent of ¹⁷⁷LuCl₃ and aqueous DOTA-TATE solution.

Preparation of a patient dose of ¹⁷⁷Lu-DOTA-TATE

¹⁷⁷Lu-DOTA-TATE suitable for administration to the patients was prepared by adding the required volume of aqueous DOTA-TATE solution (prepared by dissolving DOTA-TATE in high-purity water with a concentration of 1 μg/μL) in the necessary volume of 0.1 M ammonium acetate buffer (pH ∼5) containing 40 mg/mL gentisic acid. The pH of the resultant solution was adjusted to 5, if required, after the addition of required volume of ¹⁷⁷LuCl₃. Subsequently, the reaction mixture was incubated at 85°C–90°C for 45 minutes. After the quality control studies, the preparation was subjected to Millipore filtration prior to the administration to the patients.

Quality control techniques

Before the preparation is administered to the patients, it is essential to perform the quality control tests to find out the extent of complexation. Quick quality control of ¹⁷⁷Lu-DOTA-TATE was performed by paper chromatography using 50% aqueous acetonitrile (v/v) as the eluting solvent. The exact complexation yield of every batch prepared was determined by HPLC using acetonitrile and water mixed with 0.1% trifluoro acetic acid as the mobile phase following the reported gradient elution technique.¹⁰

Stability studies of ¹⁷⁷Lu-DOTA-TATE patient dose

The stability of ¹⁷⁷Lu-DOTA-TATE patient dose was studied by incubating the preparation at room temperature up to 24 hours and determining its radiochemical purity at different time intervals following the quality control techniques mentioned earlier.

Results

Production of ¹⁷⁷Lu

¹⁷⁷Lu was obtained with a specific activity range of 740–1480 GBq/mg (20–40 Ci/mg) at 24 hours after end of bombardment (EOB). The variation of specific activity with which ¹⁷⁷Lu was obtained was mainly due to the use of Lu targets with different enrichment of ¹⁷⁶Lu as well as due to the fluctuation of thermal neutron flux during irradiation and unscheduled shutdown of the reactor. ^177mLu was found to be the only radionuclidic impurity present in the processed ¹⁷⁷Lu. It was observed that 5.55 kBq (0.15 μCi) of ^177mLu was present per 37 MBq (1 mCi) of ¹⁷⁷Lu at EOB, which corresponds to 0.015% of the total activity produced, indicating that the radionuclidic purity of ¹⁷⁷Lu produced was more than 99.98%.

Optimal protocol for a patient dose

For the preparation of a typical 7.40 GBq (200 mCi) patient dose of ¹⁷⁷Lu-DOTA-TATE using ¹⁷⁷Lu of specific activity of 925 GBq/mg (25 Ci/mg), the protocol to be used is as follows. It is evident that a 7.40 GBq (200 mCi) preparation will have 8 μg of Lu, which is equivalent to 0.045 μM Lu. Now, as the molar ratio of DOTA-TATE and Lu need to be 4:1 in the preparation, the amount of DOTA-TATE required will be 260 μg (molecular weight of DOTA-TATE is 1436). This implies that 260 μL of the stock solution of DOTA-TATE (1 μg/μL) will be required. Considering that the radioactive concentration of ¹⁷⁷Lu at the time of preparation is 37 GBq/mL (1 Ci/mL), 200 μL of ¹⁷⁷LuCl₃ needs to be added to prepare a 7.40 GBq (200 mCi) patient dose. Therefore, the buffer requirement will be ∼1.4 mL [(260 + 200) × 3 μL = 1380 μL]. Hence, for the actual preparation, 260 μL of DOTA-TATE stock solution is added to 1.4 mL of 0.1 M ammonium acetate buffer containing 56 mg of gentisic acid followed by 200 μL of ¹⁷⁷LuCl₃. In the final step, the reaction mixture needs to be incubated at 85°C–90°C for 45 minutes after adjusting the pH to ∼5, if necessary.

Table 1 shows the volume/weight of different constituents required for the preparation of 7.40 GBq (200 mCi) patient dose of ¹⁷⁷Lu-DOTA-TATE with variable ¹⁷⁷Lu specific activity.

Table 1.

Composition of 7.40 GBq (200 mCi) Patient Dose of ¹⁷⁷ Lu-DOTA-TATE with Variable ¹⁷⁷ Lu Specific Activity

Specific activity of ¹⁷⁷Lu (GBq/mg [Ci/mg])	Required amount of DOTA-TATE (μg [μmol])	Required volume of buffer (mL)	Required amount of gentisic acid (mg)	Total volume of the preparation (mL)	Specific activity of the preparation (GBq/μmol [mCi/μmol])
740 (20)	324 (0.226)	1.57	63	2.10	32.74 (885)
925 (25)	259 (0.181)	1.38	55	1.84	40.88 (1105)
1110 (30)	216 (0.151)	1.25	50	1.66	49.01 (1325)
1295 (35)	185 (0.129)	1.16	46	1.54	57.36 (1550)
1480 (40)	162 (0.113)	1.09	43	1.45	65.49 (1770)

Volume of ¹⁷⁷Lu is considered as 0.2 mL in all the cases.

Quality control of ¹⁷⁷Lu-DOTA-TATE

In PC using 50% aqueous acetonitrile (v/v), it was observed that the activity corresponding to ¹⁷⁷Lu-DOTA-TATE moved toward the solvent front (R _f = 0.5–0.8), whereas uncomplexed ¹⁷⁷Lu remained at the point of spotting (R _f = 0–0.1) under identical conditions. Typical PC patterns of ¹⁷⁷Lu-DOTA-TATE and ¹⁷⁷LuCl₃ are shown in Figure 1A and B, respectively. Though paper chromatography was used as a quick quality control measure for deciding the suitability of the preparation for patient application, actual complexation yield was determined by HPLC studies, which were performed subsequently for each batch. Figure 2A and B show the typical HPLC patterns of ¹⁷⁷Lu-DOTA-TATE complex after preparation and 7 days postpreparation, respectively. It was observed that ¹⁷⁷Lu-DOTA-TATE was obtained in near-quantitative yield following the developed protocol.

FIG. 1.

Typical paper chromatography patterns of ¹⁷⁷Lu-DOTA-TATE (A) and ¹⁷⁷LuCl₃ (B) in 50% aqueous acetonitrile (v/v).

FIG. 2.

Typical HPLC patterns [CPS versus retention time (min)] of ¹⁷⁷Lu-DOTA-TATE complex (A) after preparation and (B) 7 days postpreparation.

Stability studies of ¹⁷⁷Lu-DOTA-TATE patient dose

It was observed that the preparation was adequately stable up to 7 days at room temperature as no appreciable reduction of radiochemical purity of the agent was detected.

Discussion

It has been well documented in the literature that the receptor-specific therapeutic agents need to be prepared with highest possible specific activity to achieve maximum therapeutic efficacy. The first step of achieving this is obviously the availability of ¹⁷⁷Lu with as high specific activity as practically possible during the preparation of the agent. Though nca ¹⁷⁷Lu could be obtained by indirect route involving the neutron irradiation of enriched (in ¹⁷⁶Yb) Yb₂O₃ target followed by β⁻ particle emission, this route is reported to be more cumbersome owing to the requirement of separating two adjacent members of the lanthanide series. Moreover, irradiation of highly enriched ¹⁷⁶Yb target, which possesses a poor thermal neutron capture cross-section (2.4 b), is not economical. Therefore, for the present study, the production of ¹⁷⁷Lu was envisaged via direct route involving the neutron irradiation of enriched (in ¹⁷⁶Lu) Lu₂O₃ target. It has been well reported that the irradiation time is required to be optimized to produce ¹⁷⁷Lu with highest possible specific activity following this route, particularly when the irradiation is carried out in a high-flux reactor or high-flux positions of a medium-flux reactor.¹³ It can be shown by theoretical calculation that irradiation for 21 days (each cycle of 7 days) is required to produce ¹⁷⁷Lu with maximum possible specific activity when the irradiation is being carried out in the high-flux positions of the reactor (DHRUVA).¹¹ Hence, for the preparation of the patient dose of ¹⁷⁷Lu-DOTA-TATE with highest achievable specific activity, ¹⁷⁷Lu was produced by irradiating enriched (in ¹⁷⁶Lu) Lu₂O₃ target for 21 days.

To prepare the radiopharmaceutical with highest possible specific activity at the time of administration to the patients, it is necessary to label minimum amount of DOTA-TATE using ¹⁷⁷Lu, without compromising the stability of the agent. It has been observed that when the molar ratios of DOTA-TATE and Lu are taken as 4:1, the ¹⁷⁷Lu-DOTA-TATE complex could be obtained with >98% radiochemical purity and adequate stability up to 7 days.¹⁰ Therefore, it was decided that similar molar ratios will be maintained during the preparation of patient doses of ¹⁷⁷Lu-DOTA-TATE. However, as the specific activity of ¹⁷⁷Lu available during the preparation of patient dose varies considerably, the use of a cold kit, which has a fixed amount of DOTA-TATE, may not always provide the agent with highest possible specific activity. The specific activity of ¹⁷⁷Lu varies from batch to batch because of the variation of reactor irradiation conditions such as power fluctuation, intermediate shutdown, etc., as well as because of the use of Lu₂O₃ target with different enrichment factors. Moreover, in a country like India, which has limited radioisotope production facilities, it requires few hours to 2–3 days before the radionuclide could be delivered at the hospital radiopharmacy for the preparation of radiopharmaceuticals. Therefore, depending upon the proximity of the radiotherapy centers with respect to the reactor site, different centers receive ¹⁷⁷Lu with different specific activities even when the ¹⁷⁷Lu activity is supplied to all the centers from the same batch. Hence, the use of a cold kit containing a fixed amount of DOTA-TATE is not expected to give the agent with highest possible specific activity. Therefore, there is a need of developing a simple protocol that can be followed at the hospital radiopharmacies so that the agent could be prepared with maximum possible specific activity during the time of administration.

As it is essential to ensure that the agent was prepared with desired radiochemical yield, quality control procedures must be followed before it can be administered to the patients. For this, a quick quality control method has been developed based on simple paper chromatography technique using 50% aqueous acetonitrile (v/v) as the eluting solvent. This procedure provides a fair idea about the suitability of the preparation for human administration and thus can be used as a quick quality control measure. The accurate radiochemical purity of the agent can be subsequently determined by HPLC technique.

The method described in the present article for the preparation of therapeutic doses of ¹⁷⁷Lu-DOTA-TATE at the hospital radiopharmacy has been successfully employed at five different major nuclear medicine centers of India. One hundred fifty (150) patients suffering from various types of neuroendocrine tumors have been treated using ¹⁷⁷Lu-DOTA-TATE prepared following this method and 250 patient doses have been successfully dispensed till date. Figure 3 shows representative scintigraphic images of patients with neuroendocrine-originated tumors having extensive metastases (A) and with neuroendocrine-originated tumors with lung metastases (B), recorded at 24 hours postadministration of 7.40 GBq (200 mCi) of ¹⁷⁷Lu-DOTA-TATE prepared following the developed protocol.

FIG. 3.

Typical posttherapy whole-body images of patients with neuroendocrine-originated tumors having extensive metastases (A) and neuroendocrine-originated tumors with lung metastases (B) recorded at 24 hours postadministration of 7.40 GBq (200 mCi) of ¹⁷⁷Lu-DOTA-TATE.

Conclusions

A suitable method for the preparation of patient doses of ¹⁷⁷Lu-DOTA-TATE, an agent presently being used for targeted therapy of neuroendocrine tumors overexpressing somatostatin receptors, with maximum possible specific activity during its administration to the patients has been developed. The method has the advantage of preparing the agent using the minimum amount of DOTA-TATE depending upon the available specific activity of ¹⁷⁷Lu during the time of its preparation, thereby ensuring the preparation of the agent at highest possible specific activity. Suitable, simple and rapid quality control methods were developed for carrying out quick quality control tests of the agent. This method has been successfully employed for the preparation of patient doses of ¹⁷⁷Lu-DOTA-TATE at five different major nuclear medicine centers across India and 250 patient doses have been successfully dispensed till date.

Footnotes

Acknowledgments

The authors are grateful to Mr. K.V. Vimalnath Nair for the radiochemical processing of the irradiated Lu targets and Dr. S.V. Thakare and Mr. K.C. Jagadeesan for helping in carrying out the irradiations of Lu target. The authors gratefully acknowledge Dr. V. Venugopal, Director, Radiochemistry and Isotope Group, Bhabha Atomic Research Centre, for his keen interest and constant encouragement.

Disclosure Statement

The authors disclose that there are no financial or other conflicting interests in this work.

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Preparation of Patient Doses of 177 Lu-DOTA-TATE Using Indigenously Produced 177 Lu: The Indian Experience

Abstract

Purpose:

Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Production of 177Lu

Calculation for arriving at the optimal protocol for a patient dose

Preparation of a patient dose of 177Lu-DOTA-TATE

Quality control techniques

Stability studies of 177Lu-DOTA-TATE patient dose

Results

Production of 177Lu

Optimal protocol for a patient dose

Quality control of 177Lu-DOTA-TATE

Stability studies of 177Lu-DOTA-TATE patient dose

Discussion

Conclusions

Footnotes

Acknowledgments

Disclosure Statement

References

Production of ¹⁷⁷Lu

Preparation of a patient dose of ¹⁷⁷Lu-DOTA-TATE

Stability studies of ¹⁷⁷Lu-DOTA-TATE patient dose

Production of ¹⁷⁷Lu

Quality control of ¹⁷⁷Lu-DOTA-TATE

Stability studies of ¹⁷⁷Lu-DOTA-TATE patient dose