DESCRIPTION

Thyrogen® (thyrotropin alfa for injection) contains a highly purified recombinant form of human thyroid stimulating hormone (TSH), a glycoprotein which is produced by recombinant DNA technology. Thyrotropin alfa is synthesized in a genetically modified Chinese hamster ovary cell line.

Thyrotropin alfa is a heterodimeric glycoprotein comprised of two non-covalently linked subunits, an alpha subunit of 92 amino acid residues containing two N-linked glycosylation sites and a beta subunit of 118 residues containing one N-linked glycosylation site. The amino acid sequence of thyrotropin alfa is identical to that of human pituitary thyroid stimulating hormone.

Both thyrotropin alfa and naturally occurring human pituitary thyroid stimulating hormone are synthesized as a mixture of glycosylation variants. Unlike pituitary TSH, which is secreted as a mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated but not sulfated. The biological activity of thyrotropin alfa is determined by a cell-based bioassay. In this assay, cells expressing a functional TSH receptor and a cAMP-responsive element coupled to a heterologous reporter gene, luciferase, enable the measurement of rhTSH activity by measuring the luciferase response. The specific activity of thyrotropin alfa is determined relative to an internal Genzyme reference standard that was calibrated against the World Health Organization (WHO) human TSH reference standard.

Thyrogen is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product, intended for intramuscular (IM) administration after reconstitution with Sterile Water for Injection, USP. Each vial of Thyrogen contains 1.1 mg thyrotropin alfa, 36 mg Mannitol, 5.1 mg Sodium Phosphate, and 2.4 mg Sodium Chloride.

After reconstitution with 1.2 mL of Sterile Water for Injection, USP, the thyrotropin alfa concentration is 0.9 mg/mL. The pH of the reconstituted solution is approximately 7.0.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Thyrotropin alfa (recombinant human thyroid stimulating hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. It has comparable biochemical properties to the human pituitary TSH. Binding of thyrotropin alfa to TSH receptors on normal thyroid epithelial cells or on well-differentiated thyroid cancer tissue stimulates iodine uptake and organification, and synthesis and secretion of thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4).

In patients with thyroid cancer, a near-total or total thyroidectomy is usually performed. Thyroidectomy is usually followed by radioiodine treatment to remove any remnant of normal thyroid tissue and microscopic residues of malignant tissue. Prior to radioiodine remnant ablation, serum TSH elevation is necessary to promote uptake of radioiodine by thyroid cells or thyroid cancer cells. Elevation of TSH may be achieved by withholding of synthetic thyroid hormone medication after thyroidectomy, with subsequent rise of endogenous pituitary thyroid stimulating hormone; or by administration of thyrotropin in the setting of synthetic thyroid hormone administration. After remnant ablation, patients are placed on synthetic thyroid hormone supplements to replace endogenous hormone and to suppress serum levels of TSH in order to avoid TSH-stimulated tumor growth. Thereafter, patients are followed for the presence of remnants, or of residual or recurrent cancer, by thyroglobulin (Tg) testing, usually with radioiodine imaging. This follow-up testing is most effective when conducted under TSH stimulation, achieved either by thyroid hormone withdrawal or administration of thyrotropin. Thyroid hormone withdrawal results in hypothyroidism with subsequent elevation of endogenous pituitary TSH; when thyrotropin is used, patients remain on thyroid hormone suppressive therapy and are euthyroid.

Pharmacokinetics

The pharmacokinetics of Thyrogen were studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg IM dose. Mean peak concentrations of 116 ± 38 mU/L were reached between 3 and 24 hours after injection (median of 10 hours). The mean apparent elimination half-life was 25 ± 10 hours. The organ(s) of TSH clearance in man have not been identified, but studies of pituitary-derived TSH suggest the involvement of the liver and kidneys.

Clinical Trials

Clinical Trials of Thyrogen as an Adjunctive Diagnostic Tool:

Two phase 3 clinical trials were conducted in 358 eva luable patients with well-differentiated thyroid cancer to compare 48-hour radioiodine (131I) whole body scans obtained after Thyrogen to whole body scans after thyroid hormone withdrawal. One of these trials also compared Tg levels obtained after Thyrogen to those on thyroid hormone suppressive therapy, and to those after thyroid hormone withdrawal. All Tg testing was performed in a central laboratory using a radioimmunoassay (RIA) with a functional sensitivity of 2.5 ng/mL. Only successfully ablated patients (defined as patients who have undergone total or near-total thyroidectomy with or without radioiodine ablation, and with < 1% uptake in the thyroid bed on a scan after thyroid hormone withdrawal) without detectable anti-thyroglobulin antibodies were included in the Tg data analysis. The maximum Thyrogen Tg value was obtained 72 hours after the final Thyrogen injection, and this value was used in the analysis (see DOSAGE AND ADMINISTRATION).

Diagnostic Radioiodine Whole Body Scan Results

Table 1summarizes the scan data in patients with positive scans after withdrawal of thyroid hormone from the diagnostic phase 3 studies: