Gastromark (Ferumoxsil) - Description and Clinical Pharmacology

DESCRIPTION

GastroMARK (ferumoxsil, oral suspension) is an aqueous suspension of silicone-coated, superparamagnetic iron oxide, intended for oral administration as a magnetic resonance imaging contrast media. GastroMARK is designated chemically as poly [N-(2-aminoethyl)-3-aminopropyl] siloxane coated non-stoichiometric magnetite (FeOx[C5H13N2SiO2]y), which has been manufactured to obtain a small uniform particle size of approximately 0.4 microns.

GastroMARK is a turbid, slightly viscous, dark brown to orange-brown liquid formulation prepared for oral administration. The formulation contains water, sodium chloride, sorbitol, saccharin, carboxymethylcellulose, methylparaben, propylparaben, yellow dye#6, red dye #40, and flavoring. Each milliliter of GastroMARK contains 175 micrograms of iron. Each milliliter also contains 1.4 milligrams of parabens as antimicrobial agents. The osmolality of the suspension is 250 mOsm; specific gravity is 1.01 grams per milliliter.The pH is 5.5 to 9.0, adjusted with sodium hydroxide.

The product is supplied in 360 mL bottles containing 300 mL of GastroMARK.

CLINICAL PHARMACOLOGY

General: GastroMARK is an oral aqueous suspension of a superparamagnetic magnetic resonance imaging (MRI) contrast agent. After oral administration of GastroMARK, the agent fills the stomach and small intestine by 30 to 45 minutes after ingestion. The imaging agent passes distally to the large intestine by 4 to 7 hours after ingestion. GastroMARK is primarily eliminated in the feces.

Pharmacokinetics:

Absorption: Following the administration of 600 mL of GastroMARK containing 10μCi of ₅₉Fe (105 mg of iron) to 3 healthy, male volunteers and the same GastroMARK dose containing 9.5μCi of ₅₉Fe (105 mg of iron) to 3 male patients with inflammatory bowel diseases, the blood concentration of ₅₉Fe in all subjects/patients for Days 1, 3, 7, and 14 after dosing were low (respectively, 0-0.024, 0-0.015, 0- 0.058 and 0-0.044 nCi/mL). When normalized to a 70 kg man with 5000 mL of blood for Days 1, 3, 7, and 14 after dosing, these concentrations amount to 1.3%, 0.8%, 3.0% and 2.3% of the doses of₅₉Fe administered. This study is too small to reliably predict differences in absorption between healthy people and patients with inflammatory bowel disease. Absorption of GastroMARK has not been studied in women.

Generally, the extent of absorption of iron from the gastrointestinal tract is expected to depend upon the existing body stores of iron. The lower the body iron stores, the more iron may be absorbed from GastroMARK.

Distribution and Metabolism: Iron absorbed from GastroMARK enters the hematopoietic pathway and is incorporated into the hemoglobin of the red blood cells or into ferritin for storage. The extent to which silicone is absorbed or metabolized in humans is not known.

Elimination: Unabsorbed iron in GastroMARK is eliminated in feces. Based upon literature information, iron absorbed into the blood is highly conserved. In healthy normal adult men, about 10% of the body’s iron store is lost per year (1 mg per day). Iron is excreted from the gastrointestinal tract in extravasated red cells, in bile and in exfoliated mucosal cells. Small amounts of iron are lost in the urine and in desquamated skin. Additional iron loss occurs in menstrual flow in women.

Food Effect: GastroMARK is intended for administration under fasting conditions. The effect of food on the disposition of GastroMARK has not been studied.

Special Populations: Studies have not been conducted to evaluate the disposition of GastroMARK in special populations such as patients with hepatic and renal diseases, or patients with hemochromatosis, hemosiderosis and other blood disorders.

The amount of iron absorbed in patients with active inflammatory bowel disease has not been studied adequately.

Drug-Drug Interactions: Drug interaction studies have not been conducted with GastroMARK. The effect of iron supplements or drugs that increase or decrease gastrointestinal transit time on imaging with GastroMARK has not been studied.

CLINICAL TRIALS

GastroMARK was evaluated in a total of 256 people (63 normal volunteers and 193 patients). Of these, 141 were men and 115 were women. Racial demographics were: 225 Caucasian, 22 Black, 7 Asian, and 2 from other races.

Of the above, 186 patients were enrolled in two identical clinical studies of 93 subjects each. Patients were referred for magnetic resonance imaging (MRI) and had known or suspected abdominal masses. GastroMARK was evaluated for its ability to enhance the bowel and improve the definition of anatomic markings in the MRI. Confirmation of the final diagnosis for lesions external to the bowel was not obtained.

The MRI images from the two studies were evaluated by blinded readers for bowel marking and the delineation of anatomy. The before and after GastroMARK images were rated for the percent of images that were“better, same, worse, or not evaluable.” The table below lists the percentage of patients in each study with MRIs in different regions of the abdomen that were “better” after GastroMARK. After GastroMARK, artifacts were rated as present (yes) and absent (no).

The mean volume of GastroMARK administered was 699 mL (122 mg of iron).

In comparison to GastroMARK 30 minute images of the hepatic & splenic flexure and the sigmoid, in a subset of 30 patients there is a trend towards improved contrast at 4 to 7 hours; however, these findings have not been confirmed and the impact of dilution is not known.

PATIENTS (NUMBER AND PERCENT) WITH BETTER IMAGING SCORES AFTER GASTROMARK ENHANCEMENT OF MRI T1 OR T2 NUMBER & PERCENT WEIGHTED SEQUENCES^*

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Image Sequence	T1		T2
Study ID and number of patients	Study A N=93	Study B N=93	Study A N=93	Study B N=93
IMAGING WITHIN 30 MINUTES OF GASROMARK INGESTION**
Marking of the Bowel
Upper GI Overall     Stomach     Duodenal Sweep     Jejunum& Ileum Lower GI Overall     Hepatic& Splenic Flexure     Sigmoid	54 (58%) 44 (47%) 26 (28%) 38 (41%) 23 (25%) 18 (19%) 4 (4%)	49 (53%) 58 (62%) 42 (45%) 52 (56%) 26 (28%) 25 (29%) 4 (4%)	71 (77%) 51 (55%) 50 (54%) 58 (63%) 37 (40%) 23 (25%) 10 (11%)	51 (55%) 48 (52%) 40 (43%) 68 (73%) 43 (46%) 41 (44%) 8 (9%)
Delineation of Anatomic Features
Pancreas     Anterior Kidney	15 (16%) 6 (7%)	32 (34%) 3 (3%)	32 (34%) 15 (16%)	28 (30%) 3 (3%)

After GastroMARK, depending upon the site evaluated, 11-70% of the patients had images rated ”the same” as those without GastroMARK; and 1- 3% of the patients had images rated worse or not evaluable. After GastroMARK, artifacts were seen in 1-3% of the MRI images.

The presence or absence of mass lesions was further evaluated in a subset of 67 (36%) patients (32 with pancreatic/gastric masses and 35 with possible bowel obstruction). For these patients, in comparison to MRIs before GastroMARK and depending upon the anatomic location, the visualized abnormalities on MRI images after GastroMARK increased confidence excluding the mass in 31-41% of the patients; increased confidence in delineating the mass in 44-49% of the patients; and in 16-26% of the patients the information was not helpful. Confirmation of findings or MRI images judged normal after GastroMARK was not obtained. GastroMARK was not evaluated for the contribution ot the GastroMARK MRI to the final diagnosis or patient management.