Lutetium Dotatate Lu-177
Lutetium Dotatate Lu-177 Uses, Dosage, Side Effects, Food Interaction and all others data.
A 177Lu-labeled somatostatin analog peptide, Lutetium Dotatate Lu-177 belongs to an emerging form of treatments called Peptide Receptor Radionuclide Therapy (PRRT), which involves targeting tumours with molecules carrying radioactive particles that bind to specific receptors expressed by the tumour. Lutetium Dotatate Lu-177 may also be referred to as 177Lu-DOTA-Tyr3-octreotate. Compared to the alternative somatostatin analogue DOTA-Tyr3-octreotide (dotatoc), Lutetium Dotatate Lu-177 displays higher uptake of radioactivity in tumors and better residence times . In terms of biodistribution, Lutetium Dotatate Lu-177 demonstrated a lower whole-body retention, indicating potentially lower risk for bone marrow toxicity . The presence of a radioligand allows monitoring of treatment response post therapy and prior to next fraction of the dose delivery which may be clinically beneficial in estimating the intensity of lesion uptakes or deciding the dose for subsequent administrations .
Lutetium Dotatate Lu-177 was approved by the FDA as Lutathera in January 2018 for intravenous injection. It is a first radiopharmaceutical agent to be approved for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and is indicated for adult patients with somatostatin receptor-positive GEP-NETs . Targeting pancreas and other parts of the gastrointestinal tract such as the intestines and colon, neuroendocrine tumors may commonly metastasize to metastasize to the mesentery, peritoneum, and liver . Patients with GEP-NETs have limited second-line treatment options after the metastasis of tumors and inadequate therapeutic response from first-line therapies. In a clinical trial involving patients with advanced somatostatin receptor-positive GEP-NET, the treatment of Lutetium Dotatate Lu-177 in combination with octreotide resulted in longer progression-free survival compared to patients receiving octreotide alone and there was evidence of an overall survival benefit .
Clinically significant myelosuppression occurred in less than 10% of patients in the Lutetium Dotatate Lu-177 (177Lu-Dotatate) group in one clinical trial . According to an open label study involving 20 patients with somatostatin receptor-positive midgut carcinoid tumors, the treatment with did not result in any large changes in the mean QTc interval (i.e., >20 ms) . Due to high expression of SSTR2, pancreas was the primary target in animal studies using a non-radioactive form of lutetium Lu 177 dotatate (lutetium Lu 175 dotatate) .
| Trade Name | Lutetium Dotatate Lu-177 |
| Generic | Lutetium Lu 177 dotatate |
| Lutetium Lu 177 dotatate Other Names | 177Lu-DOTA-octreotate, 177Lu-dotatate, Dotatate lutenium Lu-177, Lu-DOTA-TATE, Lutetium dotatate Lu-177, lutetium Lu 177 dotatate |
| Type | |
| Formula | C65H87LuN14O19S2 |
| Weight | Average: 1609.55 Monoisotopic: 1608.515088972 |
| Protein binding | The non-radioactive form of lutetium dotatate is 43% bound to human plasma proteins . |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Lutetium Dotatate Lu-177 is a radiolabeled somatostatin analog used to treat somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors.
Indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults .
Lutetium Dotatate Lu-177 is also used to associated treatment for these conditions: Gastroenteropancreatic Neuroendocrine Tumors
How Lutetium Dotatate Lu-177 works
Somatostatin receptors (SSRT) are inhibitory G-protein coupled receptors that are ubiquitously expressed in normal and cancer cells. The natural ligand of SSRTs, somatostatin, is a potent inhibitory regulator of pituitary and gastrointestinal hormone release and proliferation . Advanced and well-differentiated neuroendocrine tumors express high levels of somatostatin receptors, especially somatostatin recetor type 2 (SSRT2), and have the ability to incorporate amines intracellularly and decarboxylate them .
As an analogue of somatostatin, Lutetium Dotatate Lu-177 binds to somatostatin receptor with highest binding affinity for SSRT2. Upon binding to SSRT-expressing cells, including malignant somatostatin receptor-positive tumors, the radiolabelled compound is internalized and the beta emission from the radioligand Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells . As with other somatostatin analogues, Lu177 dotatate is expected to suppress excessive secretion of amines and hormones, such as serotonin, from carcinoid tumors and certain types of endocrine pancreatic tumors (glucagonoma, VIPoma and gastrinoma) . The release of peptides and other gastrointestinal hormones important in tumor growth, including gastrin, cholecystokinin and epidermal growth factor (EGF), may also be reduced through promoted somtatostatin signalling pathways.
Toxicity
While carcinogenicity and mutagenicity studies have not been conducted with lutetium 177 dotatate, radioisotope is considered a carcinogen and mutagen. No fertility studies have been performed . In repeat dose toxicity studies of rats, pancreatic acinar apoptosis occurred at lutetium Lu 175 dotatate doses ≥ 5 mg/kg. Pancreatic acinar cell atrophy also occurred in repeat dose toxicology studies in dogs at doses ≥ 500 mg/kg .
Food Interaction
No interactions found.Volume of Distribution
The mean volume of distribution is 460 L (CV 54%). Within 4 hours of administration, distribution in kidneys, tumor lesions, liver, spleen, and, in some patients, pituitary gland and thyroid was observed. High uptake of the radiolabeled peptide in the pancreas in animal biodistribution studies was observed due to high expression of SSTR2 . Co-administration of amino acids with lutetium Lu 177 dotatate may decrease the extent of drug distribution to the kidneys.
Elimination Route
At the recommended intravenous dose, the mean blood exposure (AUC) of lutetium Lu 177 dotatate was 41 ng.h/mL (coefficient of variation, or CV, 36 %). The mean maximum plasma concentration (Cmax) was 10 ng/mL (CV 50%) and was observed at the end of the intravenous infusion of lutetium Lu 177 dotatate .
Half Life
The mean (± standard deviation) effective blood elimination half-life is 3.5 (±1.4) hours and the mean terminal blood half-life is 71 (± 28) hours .
Clearance
The mean clearance (CL) is 4.5 L/h (CV 31%). Co-administration of amino acids with lutetium Lu 177 dotatate increased the mean beta-phase blood clearance of lutetium Lu 177 dotatate by 36% .
Elimination Route
Lutetium Dotatate Lu-177 predominantly undergoes renal excretion with cumulative excretion of 44% within 5 hours, 58% within 24 hours, and 65% within 48 hours following intravenous administration. Greater than 99% of total administered dose is expected to be eliminated within 14 days after administration although prolonged renal elimination is expected .
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