**[Review and Evaluation of Pharmacology and Toxicology
Data]{.underline}**

**Division of Medical Imaging and Radiopharmaceutical Drug Products**

**HFD-160**

**Reviewer: Adebayo A. Laniyonu, Ph.D.**

**[Chemical Name]{.underline}**: 2-Deoxy-2\[^18^F\] fluoro-D-Glucose

**[CAS Number]{.underline}**: 63503-8

**[Structure]{.underline}:**

![](media/image1.png){width="3.754861111111111in"
height="2.204861111111111in"}

**[Molecular Weight]{.underline}**: 181

**[Relevant IND/NDA/DMF]{.underline}** : NDA 20-306

**[Drug Class]{.underline}**: Positron Emission Tomography (PET)
Radiopharmaceutical

[**Indication**:]{.underline} Assessment of glucose metabolism

**[Clinical Formulation (and components)]{.underline}**:

**[Route of Administration]{.underline}**: Intravenous

[**Introduction/Drug History**:]{.underline}

There are published articles concerning the clinical use of \[^18^F\]FDG
in studying glucose metabolism as it relates to cardiovascular,
neurological and oncological needs from multiple centers. NDA 20-306,
sponsored by The Methodist Medical Center of Illinois was approved by
the FDA for the identification of regions of abnormal glucose metabolism
associated with foci of epileptic seizures. However, the agency has not
granted approval for other indications. PET radiopharmacueticals are
usually manufactured close to the site of use due to the relatively
short half-life of these products. Unlike a conventional application,
this review is not considering a known formulation, hence different
production pathway may impact on the purity and toxicological profile of
\[^18^F\]FDG since different PET centers are responsible for the
production. A major purpose of this survey is to review the available
scientific literature in an attempt to examine the scientific basis of
diagnostic use and, to determine whether Pharmacology/Toxicology studies
typically conducted and considered critical to support the safety of an
NDA application have been reported in the literature. This is not a
typical NDA review, because the experiments upon which the scientific
evidence are based were not conducted with NDA format in mind.
Nevertheless, all the articles were published in peer review journals
and the majority of the findings were reported from multiple
laboratories and centers. It is hoped that the review will (1) identify
the concepts that are scientifically valid and that appear to have
general support within the scientific community and (2) Identify the
areas where more information is required.

[**Previous clinical experience**:]{.underline}

\[^18^F\]FDG has been used in studying glucose metabolism as it relates
to cardiovascular, neurological and oncological needs from multiple
clinical centers. No adverse reaction to the radiopharmaceutical has
been demonstrated at clinically relevant doses.

[**Pharmacology**:]{.underline}

That FDG acts as a substrate to sequester the "hexokinase reaction"
resulting in the utilization of the accumulated FDG for imaging purposes
is generally well accepted. In its most basic concept, the biochemical
basis of the use of the 2-deoxy analogs of glucose such as FDG hinges on
having similar kinetics and biochemical properties with glucose.
\[^18^F\]FDG is transported through the cell membrane by facilitative
glucose transporter proteins (GLUTs). Within the cell, \[^18^F\]FDG is
phosphorylated to \[^18^F\]FDG-6-phosphate by the enzyme hexokinase. The
low Km of the hexokinase for \[^18^F\]FDG ensures for both rapid
phosphorylation and requirement for low \[^18^F\]FDG concentration for
the reaction. The action of hexokinase is not reversible. Moreover,
\[^18^F\]FDG-6-phosphate is a poor substrate for phosphoglucomutase,
glucose-6-phosphate isomerase or glucose-6-phosphate dehydrogenase
thereby limiting its entry into subsequent steps of glucose metabolism.
The inability of \[^18^F\]FDG-6-phosphate to act as a substrate in
glucose metabolism coupled with the negligible level of phosphatase
activity within the myocardium and the fact that the sacrolemma is
largely impermeable to charged species result in the trapping of
\[^18^F\]FDG-6-phosphate within the myocardium. Under steady state, the
rate of glucose phosphorylation is at equilibrium with the endogenous
rate of glucose utilization. Therefore, within a given tissue or
pathophysiological process, the retention and clearance of \[^18^F\]FDG
primarily reflect a tripartite dynamic balance involving glucose
transporter, hexokinase and glucose-6-phosphatase activities. Thus
\[^18^F\]FDG can be used as a proxy to track glucose utilization.
Surrogate use of \[^18^F\]FDG will work best in milieus where glucose is
the major source of metabolic fuel, there is minimal phosphatase
activity, and where glycogen synthesis from glucose is extremely low.
However, depending on the tissue or pathophysiological process under
consideration, other factors such as the glycemic state, utilization of
fatty acid as primary source of energy, concurrent glycogen synthesis
and degradation may impact on the accuracy of using FDG to measure
glucose metabolism.

Various components of the FDG biochemical pathway have largely been
verified. For example, Reivich et al. demonstrated that in vitro
incubation of ^14^\[C\]-FDG with purified hexokinase and ATP resulted in
a time-dependent formation of ^14^\[C\]-fluorodeoxyglucose phosphate
thus confirming that FDG is a substrate for hexokinase. Moreover, a
comparison of rat brain autoradiographs obtained using ^14^\[C\] FDG or
\[^18^F\] FDG for measurement of local cerebral glucose utilization
showed identical distribution that was different from that obtained with
3-O-methyl-\[^14^C\]glucose which is not a hexokinase substrate.
Theoretically, the phosphorylation rate relative to phosphatase activity
in a given organ can also be contributive to the metabolic trapping. In
rat, phosphorylation rate as determined by hexokinase activity showed
that the rank order was brain \> heart ≈ kidney \>lung \>\> liver. At
neutral ~p~H, phosphatase activity was not detected in any of the
tissues studied, and at ~p~H 6.5 (optimum ~p~H for
glucose-6-phosphatase) only the liver demonstrated significant activity
while low but "measurable" activity was seen in the kidney. In view of
the difficulty encountered in measuring phosphatase activity, it was not
surprising that the authors did not provide a rank order for phosphatase
activity. Although not explicitly stated, one can infer from the study
that the liver will show the least amount of metabolic trapping in view
of its measurable phosphatase activity coupled with low phosphorylation
rate. The high phosphorylation rate relative to the phosphatase activity
in brain and heart contributes in part to the metabolic trapping.

To allow for the quantification of glucose uptake from the accumulation
of FDG, the kinetic differences of transport and phosphorylation between
FDG and glucose are reflected in a ratio called the "lumped constant".
The mathematical derivation of lump constant is probably beyond the need
of this review. The original model as proposed by Sokoloff et al. (1997)
assumed that deoxyglucose-6-phosphate dephosphorylation is zero (that
is; irreversible metabolism occurred). Therefore, only organs with a low
rate of phosphatase activity and a known relationship between glucose
and deoxyglucose metabolism can best be studied accurately using the
deoxyglucose method (see Gjedde 1995). In the absence of
glucose-6-phosphatase, the lumped constant equals the ratio between the
net clearance of the glucose tracer and glucose. The lumped constant can
also be expressed to reflect the ratio between the unidirectional rate
of phosphorylation of the glucose tracer and the net clearance of
glucose. In situations where dephosphorylation can not be ignored or
assumed to be low, the lumped constant is modified. A number of
mathematical models are available for this purpose. Of more practical
concern is the observation that the lump constant changes with insulin
and the nutritional state (e.g. fasting and non-fasting) since it raises
the possibility that the change so produced may alter the FDG
accumulation value obtained without a corresponding effect on true
glucose accumulation.

**[Pharmacokinetics:]{.underline}**

Biodistribution studies reveal that FDG is well distributed into major
organs in the body. In a study examining the tissue distribution of
\[^18^F\]FDG in mouse, Gallagher, Fowler et al. (1977) showed that
intravenously administered \[^18^F\]FDG distributes to heart, brain,
kidney, lungs and liver. It is cleared rapidly from these organs except
the heart and brain where significant amounts relative to initial
distribution remain two hours post-injection. Analysis of the
radioactivity showed that the chemical form of the F-18 was as F-18-DG-6
phosphate in both the brain and the heart whereas, in the lungs, liver
and kidney, the unmetabolized F-18-DG predominates in the early stages
followed by increasing concentration of its phosphorylated metabolite
with time. For the brain and heart, and to a large extent the lungs,
liver and kidney the fact that significant portion of activity present
up to two hours was in form of F-18-DG-6-phosphate was said to be
indicative of metabolic trapping and reflective of endogenous glucose
utilization. The authors stated that they consistently experienced
relatively large variations in heart activities at several time
intervals for no apparent reason, however, they speculated that the
variation in activity might be related to the physiological state of the
animal at the time of injection.

Kanazawa et al. (1986) employed NMR technique to examine tissue
distribution and urinary clearance of fluorinated compounds in fasted
male mice following intravenous injection of FDG. The results indicated
that FDG is converted through phosphorylated intermediates to
2-fluoro-2deoxy-D-mannose (FDM). Unlike the study of Gallagher et al.
(1977), Kanazawa's study did not distinguish between FDG and its
phosphorylated metabolites. Two fluorinated compounds, FDG and FDM were
identified suggesting bioisomerization of FDG (6-P) to FDM (6-P) in
organs. In the brain, NMR signals were detected as early as 5 minutes
with signal intensity decreasing with time and becoming undetectable at
48 hours post-injection. The blood profile is similar to the brain's
profile. In contrast, accumulation was slower in the heart with total
signal intensity increasing up to 24 hours and decreasing thereafter.
Fluorinated compounds were still detectable in cardiac tissues up to 96
hours after administration of FDG raising the possibility that
halogenated deoxyglucose compounds may be retained in cardiac tissues
for several days following administration of FDG.

Suolinna et al. (1986) examined the biodistribution and metabolism of
\[^18^F\]FDG in Rous sarcoma tumor bearing rats. Results were
essentially as described for normal rats. The hexokinase/G-6-Pase ratio
was high in brain, heart and tumor, low in liver with intermediate
values for kidney and muscle. 90% of the \[^18^F\] was found as
\[^18^F\]FDG-6-P in brain, heart and tumor, whereas the liver and kidney
contained \[^18^F\]FDG. Some minor metabolites of \[^18^F\]FDG-6-P
identified as nucleotide-derivative of \[^18^F\]FDG were detected.
Overall, the results demonstrate that Rous sarcoma metabolizes
\[^18^F\]FDG to \[^18^F\]FDG-6-P to a similar extent as the brain and
that like the brain, Rous sarcoma has low level of phosphatase activity.

\[^18^F\]FDG is largely excreted unchanged in urine. Gallagher et al.
(1978) showed that 15-25% of the injected radioactivity was excreted in
urine of mice within 90 minutes predominantly (\>90%) as unchanged
F-18-DG. Urinary excretion was not followed beyond 90 minutes. The
appearance of F-18-DG in urine, apparently due to lack of tubular
reabsorption signifies an important difference between the renal
handling of glucose and FDG. Under normal physiological conditions,
glucose is reabsorbed by the renal proximal tubule by a carrier mediated
active transport mechanism. Work by Silverman et al. (1975) demonstrated
that 2-deoxyglucose, a structural analog of F-18-DG has a low affinity
for the glucose receptor, indicative of the requirement for the hydroxyl
group on C-2 for renal resorption. By extension, Gallagher et al. (1978)
reasoned that the results of their study denoting that F-18-DG is
excreted basically unchanged is indicative of the requirement of the
hydroxyl group on C-2 for the interaction with the receptor site and
subsequent tubular resorption, thus elucidating further the structural
requirement for sugar resorption by tubular cells.

\[^18^F\]FDG contains 2-deoxy-2chloro-D-glucose (CIDG) as an impurity.
Distribution and metabolism of CIDG are presumed to be similar to that
of \[^18^F\]FDG, and may be expected to result in intracellular
formation of 2-deoxy-2chloro6-phosho-D-glucose (CIDG-6-phosphate) and
2-deoxy-2-chloro-6-phospho-D-manose (CIDM-6-phosphate). The
phosphorylated deoxyglucose compounds are dephosphorylated, and the
resulting compounds are, (FDC, FDM, CIDG, CIDM) are presumed to leave
the cells by passive diffusion.

**[Toxicology:]{.underline}**

Two limited animal toxicity studies carried out by Reivich, Kuhl et al
(1979) did not reveal significant toxicity problems. One study consisted
of two groups of BNL strain adult mice (six in each group, sex of
animals not specified) injected intraperitoneally with FDG, 14.3 mg/kg
(1000 x human dose by weight) or with equal volume of saline at weekly
intervals for 3 weeks. The animals were allowed free access to food and
water, weighed weekly and observed. The mice were sacrificed and the
internal organs examined grossly and microscopically. The authors
reported that the weight of the treated mice remained stable and did not
differ significantly from controls, and that no abnormality (gross or
microscopically) was detected in brain, heart, spleen liver, kidneys or
lungs. The second study examined the toxicological effect of intravenous
injection of FDG, 0.72 mg/kg (50 x human dose by weight) in two adult
female beagle dogs, at weekly intervals for 3 weeks. Another dog
received equal volume of saline intravenously. Urine and blood samples
were obtained before the injection, at 2 hour and 1 & 2 weeks after
injection. "A few" cerebrospinal fluids were said to be collected.
Urinalysis was performed for physical and microscopic examination,
electrolytes, creatinine, glucose, protein, uribililogen and osmolarity.
Blood samples were analyzed for RBC, WBC, platelets, reticulocytes,
differentials, hemoglobin, hematocrit, sedimentation rate, pro-thrombin
time, osmolarity, electrolytes, glucose, urea, uric acid, creatinine,
alkaline phosphatase, LDH, SGOT, SGPT, CPK, total protein, albumin and
total bilirubin. Cerebrospinal fluid was examined for glucose, protein
and chloride. The animals were sacrificed at the end of the third week
and their internal organs examined grossly and microscopically. The
authors stated that no significant abnormalities were detected in the
blood, urine and cerebrospinal fluid, and that no significant gross or
microscopic abnormalities were present in the brain, heart, spleen,
liver, kidneys, lungs, ovaries or intestines. In a different study,
Bessell et al. (1973) injected mice and rats with FDG intraperitoneally
and estimated that the LD~50~ was 600 mg/kg in both species. Apparently,
FDG administered as a single 400mg/kg IP dose did not produce any
morphological changes in rat liver and other tissues (not stated) that
were examined. Bessell et al. (1973) also examined the effect of FDG on
the growth and survival of mouse lymphoma (L5178Y) cells in vitro. The
results suggest that FDG is cytotoxic at a concentration of 1mg/ml.

The study of Thomas and Duthie (1968) examining the usefulness of
2-deoxy-D-glucose in the evaluation of the completeness of surgical
vagotomy provided pertinent information on the clinical toxicity of
2-DG. 2-DG stimulates the vagal hypothalamic center by lowering the
intracellular glucose level, and has been used to elicit the vagal phase
of gastric secretion in rat, dog and man. After fasting for 10-20 hours,
37 patients received 50 mg/kg DG in a 25% solution ( 50,000X human PET
dose by weight) intravenously over a 10 minute period post-operatively.
Sweating, hunger and thirst that were less severe, and of shorter
duration compared with the hypoglycemic response to insulin in the same
patients were noted in 34 of the patients studied. The remaining 3
patients developed what was described by the authors as "an exaggerated
hypoglycemic like state with alteration in body temperature down to
89^o^F". One of these patients became comatose; this patient also
developed severe hypoglycemic response to insulin. The symptoms with the
exception of the alteration in body temperature were reversible by the
intravenous administration of 50% dextrose. The authors stated that
there was no evidence of hepatotoxicity in the 37 postoperative tests
although the assessment method was not described. In an earlier
unreported study mentioned in the results section, the potentially more
harmful effect of liver damage was seen in 2 patients that underwent
2-DG test preoperatively. One, on the evidence of a liver biopsy
(findings not stated), the other patient became jaundiced
postoperatively with an increase in serum transaminase levels. The
authors ascribed the liver changes to possible combined effects of
starvation, anesthesia, and 2-DG. The patient population for this study
was not reported. In another study, Gough and Keddie (1975) administered
40 mg/kg 2-DG intravenously to 25 patients after an overnight fast.
Compared with control readings, there was a statistically significant
fall in diastolic blood pressure (≈ 10 mmHg) that was not matched by a
fall in systolic pressure. Other reported side effects include sweating,
excessive hunger, somnolence, weakness, headache, thirst, nausea, and
abdominal cramp. It is noted that the doses required to elicit these
effects are far in excess of that needed for PET studies, further more,
these clinical studies examined the effects of 2-DG and not 2-FDG. How
much weight one can put on the 2-DG results for the toxicity profile of
2-FDG remains to be determined. However, it is the opinion of this
reviewer that the toxicity profile of 2-DG can provide us with a
qualitative guidance on what to expect with 2-FDG.

**[Carcinogenicity:]{.underline}**

No study addressing the carcinogenicity of FDG was identified.

**[Immunotoxicology:]{.underline}**

No study addressing the immunotoxicology of FDG was identified.

**[Reproductive Toxicology:]{.underline}**

No study addressing the reproductive toxicology of FDG was identified.

**[Genotoxicity:]{.underline}**

No study addressing the genotoxicity of FDG was identified.

**Applications:**

In view of the universality of glucose use as an energy source by the
body, and the fact that biochemical alterations occur prior to, and
concurrently with anatomical changes in many disease states,
\[^18^F\]FDG may be of help in the early detection and management of the
clinical progression of many disease states involving different body
systems.

**Cardiology**

\[^18^F\]FDG-PET has found application in assessment of myocardial
viability not withstanding the recent assertion by Clarke and Veech
(1995) that a measure of the rate of FDG accumulation in the heart may
be just that- a measure of FDG accumulation and not a measure of
metabolic rate. The procedure has been used to distinguish between
viable but dysfunctional myocardium from irreversibly ischemic,
nonviable myocardium based on pattern of myocardial metabolism. As
summarized by Gropler and Bergmann (1991), following ischemic insults,
endangered myocardium that manifests improved contractile function after
appropriate therapy is deemed viable in contrast to persistently
dysfunctional completely infarcted nonviable myocardium.

The heart aerobically utilizes a number of substrates including fatty
acids and glucose for oxidative metabolism, with free fatty acids being
the preferred energy source under non-fasting physiological conditions.
During hypoxic conditions, contributive use of glucose increases because
glucose metabolism requires less energy than that of fatty acids.
However, enhanced uptake of glucose analogs such as \[^18^F\]FDG ensue
because glucose is a less efficient energy source in the absence of O~2~
producing 3 mols of ATP per mol of glucose versus 36 mols from
completely coupled metabolism of glucose. The relationship between
\[^18^F\]FDG in the heart and cardiac utilization of glucose is probably
more complicated than surmized. As succinctly put by Tewson and Krohn
(1998) " a simple static image of FDG provides beautiful cardiac images
but its value is greatly increased when compared with another tracer".
To this end, \[^18^F\]FDG uptake imaging when combined with myocardial
regional flow measurement allows for diagnostic differentiation between
viable myocardium that can benefit from flow restoration procedures and
nonviable irreversibly damaged myocardium. Results are read in terms of
concordance or otherwise between glucose utilization as reflected in
\[^18^F\]FDG uptake and regional blood flow. Two broad categories are
generally recognized (1) Perfusion-metabolism match: where there is a
simultaneous reduction in both FDG uptake and blood flow. A match is
indicative of low likelihood that revascularization will lead to
improvement in regional myocardial contractility. (2)
Perfusion-metabolism mismatch: where there is enhanced FDG uptake and
reduced blood flow. This is indicative of a high probability of improved
myocardial contractile function following blood flow restoration. The
predictive accuracy of both scenarios is said to be greater than 70%.
The flow-metabolism mismatch pattern was observed in a chronic swine
model in which an external constrictor was placed on the left anterior
descending artery. The relationship between the uptake of FDG in the
heart and cardiac utilization of glucose for metabolism in
pathophysiological conditions is complicated and not completely
understood. As concisely put by Gould, it bears reemphasizing that "the
accuracy of judging viability with \[^18^F\]FDG may be variable, with
viable myocardium failing to take up FDG under certain conditions and
necrotic myocardium taking up FDG under others". The principal factors
impacting on the uptake process and FDG imaging pattern include glucose
level, fasting state, hormonal influence, sympathomimetic activity and
diabetes. During fasting condition, ischemic but viable myocardium
utilizes glucose as energy source to a greater extent compared to
non-ischemic myocardium that employs fatty acids as the primary energy
source. This will be reflected in increases in FDG uptake by viable
myocardium compared to normal or infarcted hearts. For example, when
plasma glucose level is adequate and insulin level is high following a
meal or oral glucose load, both normal and viable but ischemic hearts
utilize more glucose for metabolism and hence proportionately accumulate
more FDG. Infarct areas will not take up FDG. In isolated rat heart
experiments, Hariharan et al. (1995) showed that measures of myocardial
glucose uptake may underestimate true metabolic rates when insulin,
lactate and β-hydorybutyrate levels are variable.

FDG uptake alone may be useful in distinguishing between stable and
unstable angina since the later showed higher levels of accumulation
than the former (Camici et al. 1986).

Of recent, Altehoefer (1998) drew attention to imaging pattern of
patients with left bundle branch block where there is decreased
\[^18^F\]FDG relative to myocardial blood flow. Operationally referred
to as 'reversed mismatched' the pattern has been hypothesized to reflect
impaired transmembrane transport and/or phosphorylation kinetics.
Furthermore, the results have been interpreted to suggest that
\[^18^F\]FDG accumulation may be impaired independently of septal
perfusion and/or viability.

**Oncology:**

Cancerous cells are characterized by enhanced rates of glucose uptake
and metabolism compared with healthy cells. Malignant cells handle
\[^18^F\]FDG similarly to normal cells. It is transported by the same
carrier mechanisms as glucose, becomes phosphorylated, and consequently
is trapped because of low level of phosphatase activity and the fact
that it is not metabolized further. As such \[^18^F\]FDG PET has been
used as a proxy to track increased glucose utilization by malignant
tumors and thus to differentiate malignant from benign tumor, and for
the detection and staging of a variety of human malignancy.

While it is recognized that changes in the metabolic microenvironment
such as lack of oxygen and nutrient can act as overt stimuli for
increases in rate of glycolysis in malignant cells, details of the
molecular mechanisms responsible for the increases in glucose uptake are
now emerging. Factors regulating the rate of glucose utilization are
complex and show tissue to tissue variation. Theoretically, enhanced
glucose accumulation can occur because of (1) increase in the activity
of glucose transporter, (2) increase rate of phosphorylation by
hexokinase or (3) a reduction in phosphatase activity. The current
thinking is that these key regulatory steps are all impacted although it
is clear from the literature that the steps are not uniformly affected
in all forms of malignancy.

FDG-PET has been useful in the detection and staging of a variety of
malignancies including, ovarian, pulmonary, colorectal, head and neck
cancer; in differentiation of malignant tumor from benign; grading of
tumor; prediction of therapeutic response to chemotherapy, and the
proliferative activity of tumor cells. However, it is doubtful whether
the increase in FDG uptake is specific for malignancy or a distinctive
characteristic of malignant as opposed to benign tumors. It is more
likely reflecting the high rate of glucose utilization characteristic of
normal development and growth conditions. Moreover, \[^18^F\] FDG
accumulates in abscess via active uptake by phagocytes within the
abscess, and in the inflammatory cell elements associated with chronic
inflammation, blunt injury or with growth and necrosis of tumor.
\[^18^F\] FDG uptake is sometimes also a poor predictor of proliferative
activity of tumor cells. Wahl and colleagues showed that FDG uptake is
low in untreated prostate cancer, some hepatomas and human tumor
xenograft. This is probably not surprising in view of the diversity and
differences of tumors, and of the multifaceted nature of cancer as a
disease process. Cancer often involves loss of regulation, abnormal
metabolism of substrates, changes in cellular membranes and increased
and uncontrolled growth and proliferation of cells (Tewson and Krohn
1998). Be as it may, metabolic imaging of regional tumor biochemistry
and physiology done before, during and long after therapy is of
importance in helping individualized appropriate therapy for patients.

**Neurology:**

Glucose is the major substrate for brain metabolism. Therefore, FDG is
suited to measure normal glucose metabolic pattern and changes in
regional glucose metabolic pattern observed in many neurological
disorders. These include aging, Alzheimer's dementia, epilepsy, CNS
tumor, depression and stroke.

**[Overall Summary:]{.underline}**

That FDG acts as a substrate to sequester the "hexokinase reaction" is
well documented. The resultant accumulation of FDG is used for imaging
purposes by employing appropriately labeled FDG such as \[^18^F\]FDG.
Moreover, FDG-PET can detect changes in uptake pattern induced by
pathophysiological conditions, and the results can be used to determine
changes in glucose utilization pattern within tissues or organ systems.
What is less clear is the detailed clinical interpretation of the
results meaning and whether the underlying assumptions governing the
interpretations are impregnable. Although the number of both
pre-clinical and clinical publications on \[^18^F\]FDG-PET is
impressive, results interpretation is confounded by our lack of adequate
understanding of how disease conditions affect the fundamental
mechanistic assumptions governing the use of FDG. \[^18^ F\]FDG is a
glucose analogue, which concentrates in cells that rely upon glucose as
a primary energy source or whose dependence on glucose increases under
pathophysiological conditions. It is transported through the cell
membrane by facilitative glucose transporter proteins and phosphorylated
within the cell to \[^18^ F\]FDG-6-phosphate by the enzyme hexokinase.
Once phosphorylated it can not exit until dephosphorylated by
glucose-6-phosphatase. Therefore, within a given tissue or
pathophysiological process, the retention and clearance of \[^18^ F\]
FDG reflect a balance involving glucose transporter, hexokinase and
glucose-6-phosphatase activities. Thus when allowance is made for the
kinetic differences between glucose and FDG transport and
phosphorylation/dephosphorylation , as reflected in a ratio referred to
as the "lumped constant", \[^18^ F\] FDG can be used to track glucose
metabolism.

From a scientific perspective, there are still gaps in our knowledge of
how the key steps in the regulation of intracellular \[^18^ F\]
FDG-6-phosphate level such as the activities of the glucose transporter,
hexokinase and glucose-6-phosphatase are affected by disease states. For
example how fasting, diabetes or hormone levels affect FDG measurement
is not completely understood neither is it known whether these key steps
are differentially affected. Moreover, the observation that the lumped
constant changes with insulin and the nutritional state (fasting and
non-fasting) is of concern since it raises the possibility that the
changes so produced may alter the value of FDG accumulation obtained
without a corresponding effect on true glucose metabolism. Clarke and
Veech ((1995) went as far as asserting that a measure of the rate of FDG
accumulation in the heart may be just that- a measure of FDG
accumulation and not a measure of metabolic rate. However, this reviewer
believes that while details remain to be worked out, there is sufficient
conceptual understanding of the overall mechanistic process involved in
the use of \[^18^ F\] FDG to measure glucose metabolism

From a regulatory perspective, the issue of whether
pharmacology/toxicology studies typically conducted and considered
critical to support the safety of an NDA application, have been reported
in the literature was examined. No studies specifically addressing the
toxicology, carcinogenicity, genotoxicity, reproductive toxicology or
immunotoxicology of \[^18^ F\] FDG were identified in the literature.
However, extensive clinical experience, without reports of safety
related concerns, ameliorate the lack of data for the time being.

**[Recommendations:]{.underline}**

It is recommended that \[^18^F\]FDG be considered for approval for
indications associated with changes in glucose metabolism.

**[Reviewer's Signature:]{.underline}**

Adebayo, A. Laniyonu Ph.D.

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Date

**[Team Leader Concurrence:]{.underline}**

Nakissa Sadrieh Ph.D.

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Date