Thyrogen Pharmacology, Pharmacokinetics, Studies, Metabolism - Thyrotropin Alfa

Thyrogen Pharmacology, Pharmacokinetics, Studies, Metabolism - Thyrotropin Alfa

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 (T ₃ ) and thyroxine (T ₄ ).

In patients with thyroid cancer, a near total or total thyroidectomy is performed and 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 up for the presence of remnants or of residual or recurred cancer by thyroglobulin (Tg) testing while they remain on thyroid hormone suppressive therapy and are euthyroid, or by Tg testing and radioiodine imaging after thyroid hormone withdrawal. Thyrogen is an exogenous source of human TSH that offers an additional diagnostic tool in the follow-up of patients with a history of well-differentiated thyroid cancer.

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

Two phase 3 clinical trials were conducted in 358 evaluable patients with well-differentiated thyroid cancer to compare 48-hour radioiodine ( ¹³¹ l) 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).

Radioiodine Whole Body Scan Results

The following table summarizes the scan data in patients with positive scans after withdrawal of thyroid hormone from the phase 3 studies:

Across the two clinical studies, the Thyrogen scan failed to detect remnant and/or cancer localized to the thyroid bed in 16% (20/124) of patients in whom it was detected by a scan after thyroid hormone withdrawal. In addition, the Thyrogen scan failed to detect metastatic disease in 24% (9/38) of patients in whom it was detected by a scan after thyroid hormone withdrawal.

Thyroglobulin (Tg) Results:

Thyrogen Tg Testing Alone and in Combination with Radioiodine Imaging: Comparison with Results after Thyroid Hormone Withdrawal:

In Tg antibody negative patients with a thyroid remnant or cancer as defined by a withdrawal Tg ≥2.5 ng/mL or a positive scan (after thyroid hormone withdrawal or after radioiodine therapy), the Thyrogen Tg was ≥ 2.5 ng/mL in 69% (40/58) of patients after 2 doses of Thyrogen, and in 80% (53/66) of patients after 3 doses of Thyrogen. Across both dosage groups, 45% had a Tg ≥ 2.5 ng/mL on thyroid hormone suppressive therapy.

In these same patients, adding the whole body scan increased the detection rate of thyroid remnant or cancer to 84% (49/58) of patients after 2 doses of Thyrogen and 94% (62/66) of patients after 3 doses of Thyrogen.

Thyrogen Tg Testing Alone and in Combination with Radioiodine Imaging in Patients with Confirmed Metastatic Disease:

Metastatic disease was confirmed by a post-treatment scan or by lymph node biopsy in 35 patients. Thyrogen Tg was ≥ 2.5 ng/mL in all 35 patients while Tg on thyroid hormone suppressive therapy was ≥ 2.5 ng/mL in 79% of these patients.

In this same cohort of 35 patients with confirmed metastatic disease, the Thyrogen Tg levels were below 10 ng/mL in 27% (3/11) of patients after 2 doses of Thyrogen and in 13% (3/24) of patients after 3 doses of Thyrogen. The corresponding thyroid hormone withdrawal Tg levels in these 6 patients were 15.6-137 ng/mL. The Thyrogen scan detected metastatic disease in 1 of these 6 patients (see INDICATIONS AND USAGE , Considerations in the Use of Thyrogen ).

As with thyroid hormone withdrawal, the intra-patient reproducibility of Thyrogen testing with regard to both Tg stimulation and radioiodine imaging has not been studied.

Quality of Life:

Following Thyrogen, no change was observed in any of the 8 domains of the SF-36 Health Survey, a patient-administered quality-of-life measurement instrument. Following thyroid hormone withdrawal, statistically significant negative changes in quality of life parameters were observed in 4 of the 8 SF-36 domains. These 4 domains were: physical functioning, physical role, bodily pain and emotional role. No change was observed in the following scales: general health, vitality, social functioning and mental health.

Hypothyroid Signs and Symptoms:

Thyrogen administration was not associated with the signs and symptoms of hypothyroidism that accompanied thyroid hormone withdrawal as measured by the Billewicz scale. Statistically significant worsening in all signs and symptoms were observed during the hypothyroid phase (p<0.01).