Clinical Pharmacology

Pharmacodynamics

Thyrogen^® (thyrotropin alfa for injection) 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 Thyrogen 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 Thyrogen. Thyroid hormone withdrawal results in hypothyroidism with subsequent elevation of endogenous pituitary TSH; when Thyrogen is used, patients remain on thyroid hormone suppressive therapy and are euthyroid.

Pharmacokinetics

The pharmacokinetics of Thyrogen was studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg intramuscular dose ¹. 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.¹

In another study, injecting 10 U of Thyrogen daily for 1, 2, or 3 days resulted in a mean peak TSH concentration of 127 ± 19, 220 ± 46, and 224 ± 111 mU/L, respectively, within 4-6 hours after each injection.²

The figure below shows the peak TSH after 2 injections of Thyrogen, modeled from clinical study pharmacokinetics data.³

REFERENCES:

1. Thyrogen (thyrotropin alfa for injection) Package Insert. Cambridge, MA. Genzyme Corp. 2008.

2. Meier C, Braverman L, Ebner S, Veronikis I, Daniels G, Ross D, et al. Diagnostic Use of rhTSH in Patients with Thyroid Carcinoma (Phase I/II study). J Clin Endocrin Metab. 1994; 78:188-196.

3. Data on file, Genzyme Corporation.