Source: FDA, National Drug Code (US) Revision Year: 2020
The active drug substance in DaTscan is N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[123I]iodophenyl)nortropane or ioflupane I 123.
In vitro, ioflupane binds reversibly to the human recombinant dopamine transporter (DaT) (Ki = 0.62 nM; IC50 = 0.71 nM). Autoradiography of post-mortem human brain slices exposed to radiolabeled ioflupane shows concentration of the radiolabel in striatum (caudate nucleus and putamen). The specificity of the binding of ioflupane I 125 to dopamine transporter was demonstrated by competition studies with the DaT inhibitor GBR 12909 (a dopamine reuptake inhibitor), the serotonin reuptake inhibitor citalopram, and the norepinephrine reuptake inhibitor desipramine in post-mortem human brain slices exposed to radiolabeled ioflupane. Citalopram reduced binding in the neocortex and thalamus with only minor effects in the striatum. This indicated that the binding in the cortex and thalamus is mainly to the serotonin reuptake sites. Desipramine showed no effect on the level of striatal binding of ioflupane I 125, but reduced extrastriatal binding by 60 to 85%. The binding of ioflupane I 125 to the striatum was abolished in the presence of high concentrations of GBR 12909, indicating selectivity of ioflupane binding for the pre-synaptic DaT.
Following administration of DaTscan to humans, radioactive decay of the iodine 123 emits gamma radiation which can be detected externally using gamma detectors, allowing visualization of the brain striata through SPECT imaging [see Clinical Pharmacology (12.3)].
As DaTscan contains a very small quantity of ioflupane, no ioflupane pharmacologic effects are expected [see Description (11)].
The pharmacokinetics of ioflupane I 123 were studied by monitoring radioactivity following intravenous injection; only 5% of the administered radioactivity remained in whole blood at 5 minutes post-injection. Uptake in the brain reached approximately 7% of injected radioactivity at 10 minutes post-injection and decreased to 3% after 5 hours; striata to background ratios were relatively constant between 3 and 6 hours post-injection. About 30% of the whole brain radioactivity was attributed to striatal uptake. By 48 hours post-injection, approximately 60% of the injected radioactivity has been excreted in the urine, with fecal excretion estimated to be approximately 14%.
Studies on reproductive toxicity have not been conducted. Ioflupane showed no evidence of mutagenic potential in in vitro or in vivo mutagenicity studies. Studies to assess the carcinogenic potential of ioflupane have not been performed.
Single- and repeated-dose intravenous toxicity studies have been performed using ioflupane in rats, rabbits, and dogs. Additionally, single-dose acute toxicity studies have been performed in cynomolgus monkeys. No mortality or other toxicity was observed at doses up to 5,500 times the maximum clinical dose of DaTscan; at doses greater than 1,500 times the maximum clinical dose, pharmacological responses such as mydriasis and hyperactivity were seen in some species.
The safety and efficacy of DaTscan were evaluated in two multicenter, single-arm studies (Study 1 and Study 2) that evaluated 284 adult patients with tremor. In the studies, DaTscan image outcomes were compared to a reference clinical diagnostic standard of “PS” or “non-PS”. The reference clinical diagnostic standard for “PS” consisted of the following diagnoses: Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). These three conditions have been associated with dopaminergic neurodegeneration and DaTscan imaging was not designed to distinguish among the conditions. The reference clinical diagnostic standard for “non-PS” consisted of an essential tremor (ET) diagnosis or other non-PS diagnosis. Three to 6 hours after DaTscan administration, subjects underwent SPECT imaging with a variety of multi-headed cameras or a multi-detector single-slice systems. The median administered activity evaluated in clinical studies was 173 MBq (4.7 mCi) [range, 88 to 287 MBq (2.4 to 7.8 mCi)].
DaTscan images were evaluated by readers blinded to clinical information. Study 1 readers had no other role in patient assessment; Study 2 readers included site investigators. The reference clinical diagnostic standards were the clinical diagnoses established by a consensus panel of movement disorder specialists that evaluated data inclusive through 36 months of follow-up (Study 1) or the investigator-determined baseline clinical diagnosis (Study 2). Study 1 consisted of patients with early features of Parkinsonism; patients with features suggestive of MSA or PSP were excluded. Study 2 consisted of patients with clinically established diagnosis of PS (PD, MSA, PSP) or ET.
Among the 99 patients in Study 1, 44% were female, 42% were aged 65 or over and all were Caucasian; among the 185 patients in Study 2, 35% were female, 48% were aged 65 or over and 99% were Caucasian. Among the patients in Study 1, the baseline clinical diagnoses consisted of: probable PD (44%), possible PD (31%), “benign” PD (6%), possible ET (11%), and other diagnoses (7%). Among the patients in Study 2, the baseline clinical diagnoses consisted of: PD (70%), ET (15%), MSA (10%), and PSP (5%).
Table 4 shows the positive percent agreement and negative percent agreement of the DaTscan image results with the reference clinical diagnostic standard. Positive percent agreement represents the percent of patients with abnormal DaTscan images among all the patients with a clinical diagnostic reference standard of PS. The negative percent agreement represents the percent of patients with normal DaTscan images among the patients with a non-PS clinical diagnostic reference standard.
Table 4. Positive and Negative Percent Agreements for Studies 1 and 2:
| Positive percent agreement (95 % CI) (% patients with an abnormal DaTscan image among patients with PS) | Negative percent agreement (95 % CI) (% patients with a normal DaTscan image among patients with non-PS) | |
|---|---|---|
| Study 1 (patients with early signs and/or symptoms of PS) | ||
| Reader A, n=99 | 77 (66, 87) | 96 (82, 100) |
| Reader B, n=96 | 78 (66, 87) | 96 (82, 100) |
| Reader C, n=98 | 79 (67, 87) | 96 (82, 100) |
| Study 2 (patients with established diagnoses of PS or ET) | ||
| Reader A, n=185 | 93 (88, 97) | 96 (81, 100) |
| Reader B, n=185 | 97 (93, 99) | 74 (54, 89) |
| Reader C, n=185 | 96 (92, 99) | 85 (66, 96) |
| Reader D, n=185 | 92 (87, 96) | 93 (76, 99) |
| Reader E, n=185 | 94 (90, 97) | 93 (76, 99) |
The effectiveness of DaTscan as a screening or confirmatory test and for monitoring disease progression or response to therapy has not been established.
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