Mechanism Of Action
Iobenguane is similar in structure to the antihypertensive drug guanethedine and to the neurotransmitter norepinephrine (NE). Iobenguane is, therefore, largely subject to the same uptake and accumulation pathways as NE. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and stored in the presynaptic storage vesicles. Iobenguane accumulates in adrenergically innervated tissues such as the adrenal medulla, salivary glands, heart, liver, spleen and lungs as well as tumors derived from the neural crest. By labeling iobenguane with the isotope iodine 123, it is possible to obtain scintigraphic images of the organs and tissues in which the radiopharmaceutical accumulates.
AdreView is a diagnostic radiopharmaceutical which contains a small quantity of iobenguane that is not expected to produce a pharmacodynamic effect [see DESCRIPTION]. To minimize radiation dose to the thyroid gland, this organ should be blocked before dosing [see DOSAGE AND ADMINISTRATION]. Since iobenguane is excreted mainly via the kidneys, patients with severe renal insufficiency may experience increased radiation exposure and impaired imaging results. Frequent voiding should be encouraged after administration to minimize the radiation dose to the bladder [see WARNINGS AND PRECAUTIONS]. The calculation of the estimated radiation dose is shown in Table 2 [see DOSAGE AND ADMINISTRATION].
Iobenguane is rapidly cleared from the blood and accumulates in adrenergically innervated tissues [see Mechanism Of Action]. Retention is especially prolonged in highly adrenergically innervated tissues (e.g., the adrenal medulla, heart, and salivary glands).
The majority of the iobenguane dose is excreted unaltered by the kidneys via glomerular filtration. A rapid initial clearance of circulating iobenguane is observed, followed by a slow clearance as iobenguane is released from other compartments. In patients with normal renal function, 70 to 90% of the administered dose is recovered unaltered in urine within 4 days. Iobenguane is not cleared by dialysis [see WARNINGS AND PRECAUTIONS]. Most of the remaining radioactivity recovered in the urine is in the form of the radioiodinated metabolite m-iodohippuric acid (MIHA) (typically ≤ 10%) and free radioiodide (typically ≤ 6%). The enzymatic process responsible for metabolism has not been well characterized and the pharmacologic activity of these metabolites has not been studied. Only a small amount (< 1%) of the injected dose is eliminated via the feces.
Animal Toxicology And/Or Pharmacology
Iobenguane sulfate testing in dogs revealed electrocardiographic (ECG) changes after administration of 202 times the mg/m2 conversion of the maximum human dose for a 60 kg adult; the no observable effect level (NOEL) was not determined. When iobenguane was tested in a cell system stably expressing hERG-1 potassium channels, inhibition of potassium channels was not observed at an 80 μM iobenguane concentration and the IC50 was 487 μM.
Pheochromocytoma And Neuroblastoma
The safety and efficacy of AdreView were assessed in an open-label, multicenter, multinational trial of 251 subjects with known or suspected neuroblastoma or pheochromocytoma. Diagnostic efficacy for the detection of metabolically active neuroblastoma or pheochromocytoma was determined by comparison of focal increased radionuclide uptake on planar scintigraphy at 24 ± 6 hours post-administration of AdreView against the definitive diagnosis (standard of truth). Anterior and posterior planar whole-body images, or alternatively whole-body overlapping spot images, were acquired from the head to below the knees. Additional spot images were performed as deemed appropriate at the discretion of the clinical image reviewer. SPECT imaging of the thorax and abdomen was then obtained when possible.
Of the 251 subjects dosed with AdreView, 100 had known or suspected neuroblastoma and 151 had known or suspected pheochromocytoma. The population included 154 adults and 97 pediatric patients; the majority of adults were female (59%), the majority of pediatric subjects were male (58%). The adult subjects had a mean age of 49 years (range 17 to 88 years). The pediatric patients (56 males and 41 females) consisted of 32 infants (1 month up to 2 years of age), 62 children (2 years up to 12 years) and three adolescents (12 years up to 16 years).
The definitive diagnosis (standard of truth) for the presence or absence of metabolically active pheochromocytoma or neuroblastoma was determined by histopathology or, when histopathology was unavailable, a composite of imaging (i.e., CT, MRI, [131I]-mIBG scintigraphy), plasma/urine catecholamine and/or catecholamine metabolite measurements, and clinical follow-up.
A standard of truth was available for 211 subjects (127 with pheochromocytoma, 84 with neuroblastoma) and this group comprised the diagnostic efficacy population. For 93 of these subjects, the standard of truth was based solely upon histopathology. Of 211 subjects in the efficacy population, all had planar scintigraphy and 167 subjects had SPECT in addition to planar imaging. All images were assessed independently by three readers blinded to all clinical data. Table 5 summarizes the AdreView performance characteristics, by reader.
Table 5. AdreView Planar Imaging: Sensitivity and Specificity
|Outcome||Reader A||Reader B||Reader C|
|Sensitivity (n = 159)|
|95% confidence interval||0.73 -0.86||0.70 -0.84||0.71 -0.85|
|Specificity (n = 52)|
|95% confidence interval||0.63 -0.87||0.59 -0.84||0.55 -0.81|
Performance characteristics (sensitivity and specificity) of AdreView planar imaging in patients with known or suspected neuroblastoma were similar to those in patients with known or suspected pheochromocytoma. Among the selected patients who also underwent SPECT imaging, similar performance characteristics of AdreView scintigraphy were observed when SPECT plus planar imaging was compared to planar imaging alone.
Congestive Heart Failure
The safety and efficacy of AdreView were evaluated in two open label, multicenter trials in patients with New York Heart Association (NYHA) class II or III heart failure and left ventricular ejection fraction ≤ 35%. The trials excluded subjects with an acute myocardial infarction within the prior thirty days, subjects with a functioning ventricular pacemaker as well as subjects who had received defibrillation to treat a previous arrhythmic event. Subjects underwent AdreView myocardial imaging (planar and SPECT) and continued standard clinical care; AdreView results were not used in a patient’s clinical care. Mortality was assessed for up to two years after AdreView imaging and the results from the trials were analyzed using a pre-specified data integration plan.
AdreView images in each trial were reviewed by three independent readers who assessed the H/M ratio on 3 hour 50 minute post-injection planar scintigraphy. Readers were masked to clinical information and the majority read value was used in analyses. The prognostic performance of the H/M ratio in estimating mortality was analyzed using the pre-specified 1.6 ratio cut-point to distinguish patients with higher risk from those with lower risk; other cut-points were also analyzed.
Within the two trials, 964 patients were enrolled; 80% were men, 83% were categorized as NYHA class II and 17% as class III. The average age was 62 years (range 20 -90 years of age). Most patients had ischemic heart disease (66%) and a history of smoking (74%). The patients were on a stable regimen of cardiovascular medications, including angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) (93%) and beta-blockers (92%). The range of AdreView H/M ratios in these subjects was 1.0-2.4 [mean 1.4 (± 0.2 standard deviation)].
Within the two trials, 94 age-matched control subjects without heart disease were enrolled, 64% were men, average age was 59 years (range 29 -82 years of age). The range of AdreView H/M ratios in these subjects was 1.1-2.4 [mean 1.8 (± 0.2 standard deviation)].
One Year Results: By 12 months following enrollment, 50 (5%) patients had died, 61 (6%) had missing follow-up information and three patients had missing H/M ratios.
Two Year Results: By 23 months following enrollment (the requirement for designation of two-year follow-up), 96 (10%) patients had died, 201 (21%) patients had missing follow-up information and three patients had missing H/M ratio data.
Table 6 summarizes the mortality results by categories of H/M ratio.
Table 6. AdreView H/M Ratios and One and Two Year* Mortality Rates
|Range of H/M Ratio Values (number of patients)||One-year Mortality Rate (%) (95% confidence interval)||Two-year* Mortality Rate (%) (95% confidence interval)|
|≥ 1.6 (201)||1.0 (0.0, 2.4)||3.3 (0.7, 5.9)|
|1.2 â€“ 1.6 (668)||5.5 (3.8, 7.3)||11.5 (9.0, 14.0)|
|< 1.2 (92)||13.4 (6.4, 20.5)||22.0 (13.2, 30.8)|
|*Calculated at 23 months based upon protocol definition for 2-year follow-up|
H/M Ratio Prognostic Performance Characteristics
Follow-up mortality results were used to estimate the baseline H/M ratio prognostic performance characteristics. In these estimates, various H/M ratio “cut points” were used to group patients into those with higher versus lower H/M values, such as < 1.6 versus ≥ 1.6. The group of patients who died was examined to determine the probability of these patients having had a lower baseline H/M ratio (sensitivity). The group of patients who survived was examined to determine the probability of these patients having had a higher baseline H/M ratio (specificity). Based upon these results, the prognostic usefulness of any given H/M ratio in a patient was estimated by the positive predictive value (PPV) and the negative predictive value (NPV). The PPV is the probability of death given a lower H/M ratio; the NPV is the probability of survival given a higher H/M ratio.
Table 7 summarizes the performance characteristics by various H/M ratio categories for one year, the time point with the most complete data. Results were similar for the two year follow-up time point analyses.
Table 7. One Year Mortality Outcomes and AdreView Prognostic Performance Characteristics
|H/M Group*||Subjects (n = 961)||Death**||Survival||Sensitivity (%)||Specificity (%)||PPV (%)||NPV (%)|
|*subjects grouped by H/M ratio cut-off values;|
**6% discontinued patients are counted as survived (non-events)
Cox Proportional Hazards Analyses
The association of potential risk factors with mortality for up to two years was analyzed in Cox multivariate proportional hazard modeling that included such variables as demographics, hypertension, dyslipidemia, diabetes, cardiovascular medications, smoking, and NYHA classification. The initial model included all pre-specified variables except for H/M ratio and used backward selection of variables found to be significant risk factors of all-cause mortality (p < 0.05) for inclusion in the final model. The final model consisted of the significant variables from the initial model plus the H/M ratio. In addition to age, in the final model, the H/M ratio was found to be a significant risk factor for mortality (Hazard Ratio < 0.08, p < 0.001). Left ventricular ejection fraction and brain natriuretic peptide (BNP) were not included in these models, and AdreView SPECT defect scores were not tested in these models.