martes, 14 de junio de 2016

Clinical Pharmacology Corner: FDA Approves NETSPOT (kit for preparation of gallium Ga 68 dotatate injection)

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FDA Approves NETSPOT (kit for preparation of gallium Ga 68 dotatate injection) for Intravenous Use
On June 1, 2016, the U.S. Food and Drug Administration (FDA) approved NETSPOT (kit for the preparation of gallium Ga 68 dotatate injection), a radioactive diagnostic agent. NETSPOT, after radiolabeling with Ga 68, is indicated for use with positron emission tomography (PET) imaging, for the localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients. The approved recommended amount of radioactivity to be administered for PET Imaging in adults or pediatric patients is 2 MBq/kg (0.054 mCi/kg up to 200 MBq (5.4 mCi)). Administer Ga 68 dotatate as a single injection (bolus). Patients should drink as much water as possible prior to administration of Ga 68 dotatate, and void frequently during the first hours following administration to reduce radiation exposure. 
The uptake of Ga 68 dotatate reflects the level of somatostatin receptor density in NETs. However, uptake can also be seen in a variety of other tumor types (e.g. those derived from neural crest tissue). Increased uptake might also be seen in other pathologic conditions (e.g. thyroid disease or subacute inflammation) or might occur as a normal physiologic variant (e.g. uncinate process of the pancreas). The uptake may need to be confirmed by histopathology or other assessments.
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Ga 68 dotatate 
  • MOA: Ga 68 dotatate has affinity for somatostatin subtype 2 receptors (SSTR2) and binds to cells that express somatostatin receptors, including malignant cells which overexpress SSTR2 receptors.
  • Distribution: Ga 68 dotatate distributes in all SSTR2-expressing organs (e.g., pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate, liver, salivary glands). No uptake occurs in the cerebral cortex or heart and low uptake occurs in thymus and lung.
  • Excretion: About 12% of Ga 68 dotatate is excreted in urine in the first 4 hours post-administration. 
Drug Interaction Potential
Non-radioactive somatostatin analogs competitively bind to SSTR2 and can interfere with Ga 68 dotatate imaging. Patients should be imaged with Ga 68 dotatate just prior to dosing with long-acting analogs of somatostatin. Short-lived analogs of somatostatin can be used up to 24 hours before the imaging study with Ga 68 dotatate.
Safety and Efficacy
The efficacy of NETSPOT was established in three open label single center studies (Studies A-C). 
In Study A, 97 adult patients with known or suspected neuroendocrine tumors (NETs) (mean age 54; 41 men and 56 women) were studied. The Ga 68 dotatate images were read by two independent readers blinded to clinical information. The reads were compared to a reference standard consisting of CT or MR, and to indium In 111 pentetreotide images obtained within previous 3 years. Among 78 patients in whom the reference standard and In 111 pentetreotide images were available, Ga 68 dotatate PET was in agreement with the reference standard in 74 patients (95%). Out of 50 patients with NETs localized by the reference standard, Ga 68 dotatate was positive in 48 patients including 13 patients in whom In 111 pentetreotide was negative. Ga 68 dotatate was negative in 26 out of 28 patients in whom the reference standard was negative. 
Study B was a published study which involved 104 patients (mean age 58; 52 men and 52 women) with suspected NETs due to clinical symptoms, elevated levels of tumor markers, or indeterminate tumors suggestive of NET. NET sites were localized by reference standard in 36 patients (all by histopathology). Out of these, Ga 68 dotatate was positive, correctly identifying a NET site, in 29 patients and was falsely negative in seven. In 68 patients with no NET identified by a reference standard, the images were negative in 61 and falsely positive in seven patients. 
Study C was a published study which involved 63 patients (mean age 58; 34 men and 29 women) evaluated for NET recurrence using a reference standard as described for Study B. Ga 68 dotatate images were interpreted independently by two central readers blinded to clinical information. Reader 1 correctly localized NETs in 23 out of 29 reference standard-positive patients and reader 2 correctly localized NETs in 22 such patients. In 34 patients with no NET identified by a reference standard, reader 1 was correct in 29 patients and reader 2 in 32. 
The safety of Ga 68 dotatate was evaluated in three single center studies and in a survey of the scientific literature. No serious adverse reactions were identified.

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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
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