**Review and Evaluation of Pharmacology and Toxicology Data**

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

**HFD-160**

**Nakissa Sadrieh, Ph.D.**

**Chemical name**: O-15 labeled Water

**CAS number:**

**Structure:**

**Molecular Weight:** 17

**Drug Class:** PET imaging agent

**Indication:** Measurement of cerebral blow flow

**Clinical Formulation (and components):**

H~2~ ^15^O is normally produced in a cyclotron by bombarding nitrogen
gas with deuterons followed by palladium-catalyzed reduction of ^15^O~2~
gas with hydrogen gas in order to finally obtain a saline solution. H~2~
^15^O is therefore expected to be in a 0.9% NaCl solution, with minor
contaminants produced during its synthesis. It should be noted that in
the published literature, the composition of the H~2~ ^15^O formulation,
including the amounts of the residual impurities is seldom indicated.
Therefore, at present one cannot conclude which impurities are
consistently going to be present in a preparation of H~2~ ^15^O, and in
what amounts.

**Route of Administration:** Intravenous

**Studies reviewed within this submission:**

A survey of the available literature on the use of H~2~ ^15^O was
carried out. No specific studies were identified, which could be
considered as official pharmacology or toxicology studies.

**Introduction/Drug History:**

^15^O-Water (H~2~ ^15^O) is a diffusible radioactive drug (with high
extraction ratio within a tissue) used in Positron Emission Tomography
(PET). Because it is washed out in proportion to the regional blood flow
and its kinetics are not affected by metabolism H~2~ ^15^O can be used
to assess blood flow. Most articles report on the use of H~2~ ^15^O for
the quantitation of cerebral blood flow, however, since the drug is a
general marker of flow, it is conceivable that H~2~ ^15^O may be used
for the assessment of blood flow in other organs, such as the
myocardium. Since H~2~ ^15^O is not trapped and retained in the tissue
being imaged, it promptly begins to be washed out as it enters the
tissue of interest. The t ½ of ^15^O is 2.1 minutes (122.5 seconds).

**Previous clinical experience:**

Please refer to supervisory medical officer review.

**PHARMACOLOGY**

A study published by Bergmann et al. (1989) in the Journal of the
American College of Cardiology entitled "Noninvasive quantitation of
myocardial blood flow in human subjects in with oxygen 15-labeled water
and positron emission tomography", reports a validation study conducted
in18 mongrel dogs. Twenty to 30 mCi of H~2~ ^15^O was administered
intravenously as a bolus over 3 to 5 seconds. Tomographic acquisition
was initiated at the time of administration of the H~2~ ^15^O bolus and
continued for 90 seconds. Data were processed in 5 second frames. The
dogs were anesthetized, intubated and ventilated with room air. Ten dogs
without coronary instrumentation were studied at rest, after coronary
hyperemia induced with dipyridamole or after global low flow (with
propranolol). In five other intact dogs, regional ischemia was induced.
Thrombosis was initiated in the left anterior descending coronary artery
with an intracoronary copper coil. In 3 additional intact dogs, coronary
stenosis of 50%-70% diameter narrowing was induced by placement of an
intracoronary plastic stenosis in the left anterior descending coronary
artery after anticoagulation with heparin IV. The blood flow obtained
with PET was compared with that obtained with radiolabeled 15 µm
microspheres administered to the same dogs after the completion of data
collection from H~2~ ^15^O.

***Tomographic estimates of myocardial blood flow in dogs:***

Myocardial blood flow was estimated using the one-compartment Kety
model. The assumptions underlying the use of the one-compartment Kety
model for the measurement of myocardial blood flow are the following: 1)
the uptake of tracer into tissue is flow dependent and not diffusion
limited, 2) no arteriovenous shunts or bypasses are present, 3) the
solubility of tracer must be constant, and 4) the flow must be constant
and homogenous throughout the sampled myocardial region interrogated.

The myocardial blood flow determined with PET was compared with that
obtained with microspheres in control dogs at rest, or in dogs with
coronary artery occlusion or stenosis studied at rest and after
dipyridamole administration, and in dogs with global flow decreased by
hypotension. The correlation over the flow range of 0.29 to 5.04 ml/g
per min determined with microspheres was 0.95. The following figure
shows the correlation.

![](media/image1.png)

Therefore, flow calculated with PET is reported to be closely correlated
with flow measured with microspheres.

However, the authors report that absolute flow was not measurable in
ischemic regions with positron emission tomography due to 1) a low
number of true counts in the region as a result of ischemia, 2)
decreased myocardial count recovery secondary to wall thinning, and 3)
greater influence of count spillover into ischemic, thinned regions from
blood as well as from adjacent normal myocardium. To determine the
predominant effect, global low flow was induced in 3 dogs without
regional ischemia. The flow determined using PET averaged 0.27 ± 0.10
ml/g/min and that determined with microspheres was 0.33 ± 0.03 ml/g/min.

***[Additional studies using O-15 in conjunction with PET
imaging:]{.underline}***

Three additional publications (Heiss et al., 1994, Young et al., 1996
and Pappata et al., 1993) were reviewed for possible information with
regards to PET imaging and O-15-water in animal models. In these
articles, PET was used to image hemodynamic and metabolic
characteristics of cerebral regions following middle cerebral artery
occlusion in cats and baboons. However, none of the articles contained
data on O-15-water. Rather, the studies were conducted with O-15-labeled
CO2, O2 and CO, which was administered to the animals by inhalation.
Therefore these studies will only be cited in this review and not
reviewed in detail.

## Pharmacokinetics/Toxicokinetics

There were no studies identified that reported on the pharmacokinetics
of O-15 water in animals. It is not expected that the distribution and
elimination of O-15 water would be significantly different from that of
water, namely renal and pulmonary. It should be noted that the very
short half-life of O-15 precludes a detailed study of the PK of O-15
water in animals or humans. For additional information, please refer to
the clinical pharmacologist's review.

## TOXICOLOGY

**Carcinogenicity:**

No studies assessing the carcinogenicity of H~2~ ^15^O were identified,
nor would any studies be expected to be conducted.

**Immunotoxicology:**

No studies assessing the immunotoxicity of H~2~ ^15^O were identified,
nor would any studies be expected to be conducted.

**Reproduction toxicology:**

No studies assessing the developmental toxicity of H~2~ ^15^O were
identified, nor would any studies be expected to be conducted.

**Genotoxicology:**

No studies assessing the genotoxicity of H~2~ ^15^O were identified.

**Overall Summary:**

A review of available literature on applications of H~2~ ^15^O in
conjunction with PET imaging did not reveal specific concerns from the
pharmacology and toxicology stand point. No pharmacology or toxicology
studies typically considered crucial for the support of safety of an NDA
application, were included in the literature articles reviewed. The
publications were primarily focused on illustrating the efficacy of H~2~
^15^O as a PET imaging tool for the determination of primarily cerebral
blood flow, and possible myocardial blood flow. The primary aim of the
published studies was therefore to diagnose blood flow abnormalities
associated with certain disease states.

Possible toxicology concerns may arise, depending on the presence of
residual impurities. These residual impurities in a formulation of H~2~
^15^O may vary foem batch to batch and from center to center, therefore
one cannot speculate on their potential toxicities. These impurities
would have to be identified and quantitated on a case by case basis. The
review of the synthetic procedures and the determination and
quantification of the residual impurities in H~2~ ^15^O is expected to
be determined by the reviewing chemist. If the residual impurities
identified by the reviewing chemist are of known origin, and identical
to those currently allowed in drug products, then they are expected to
be subject to the published ICH guidelines for solvents. In the event
that the identified residual impurities are present in larger quantities
than those currently permitted in drug products, then appropriate
pharmacology and toxicology studies may be warranted. This determination
will be made if the reviewing chemist for an H~2~ ^15^O application
determines that the impurities are in excess of the allowable limits.
The chemist will then consult with the pharmacology reviewer who will
determine the need for appropriate animal studies.

**Recommendations:**

No studies were identified in the published literature, which contained
pharmacology and toxicology data typically considered critical to the
evaluation of and NDA application. There are however no pharmacology
concerns regarding the use of H~2~ ^15^O in PET imaging. Toxicological
concerns may arise if the drug formulation contains residual impurities
that are in excess of those presently permissible under ICH guidelines
(please refer to the chemist's review). The identification of these
impurities in the formulation(s) of H~2~ ^15^O is expected to be carried
out by the reviewing chemist. Potential toxicology studies will be
determined by the pharmacology reviewer, as needs be.

It is recommended that H~2~ ^15^O be considered for approval for the
measurement of cerebral blood flow.

**References:**

1.  Bergmann SR, Herrero P, Markham J, Weinheimer C, Walsh MN,
    Noninvasive quantitation of myocardial blood flow in human subjects
    with Oxygen-15-labeled water and positron emission tomography, JACC,
    14:3, 639-652, 1989.

2.  Heiss WD, Graf R, Weinhard K, Lottgen J, Saito R, Fujita T, Rosner G
    and Wagner R, Dynamic penumbra demonstrated by sequential
    multitracer PET after middle cerebral artery occlusion in cats. J.
    Cerebral Blood Flow and Metabolism, 14:892-902, 1994.

3.  Young AR, Sette G, Touzani O, Rioux P, Derlon JM, MacKenzie ET and
    Baron JC, Relationship between high oxygen extraction fraction in
    the acute stage and final infarction in reversible middle cerebral
    artery occlusion: an investigation in anesthetized baboons with
    positron emission tomography. J. Cerebral Blood Flow and Metabolism,
    16:1176-1188, 1996.

4.  Pappata S, Fiorelli M, Rommel T, Hartmann A, Dettmers C, Yamaguchi
    T, Chabriat H, Poline JB, Crouzel C, Di Giamberardino L and Baron
    JC, PET study of changes in local brain hemodynamics and oxygen
    metabolism after unilateral middle cerebral artery occlusion in
    baboons. J. Cerebral Blood Flow and Metabolism, 13:416-424, 1993.

**Reviewer Signature** **Team Leader Concurrence**