Action And Clinical Pharmacology
Mechanism of Action
GENOTROPIN (somatropin for injection) is a polypeptide hormone of recombinant DNA origin. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin. GENOTROPIN stimulates linear growth in children with growth hormone deficiency. In vitro, preclinical and clinical tests have demonstrated that GENOTROPIN is therapeutically equivalent to pituitary growth hormone and achieves similar pharmacokinetic profiles in normal adults.
Treatment of growth hormone deficient (GHD) children with GENOTROPIN produces increased growth rate and IGF – I (Insulin like Growth Factor- I) concentrations that are similar to those seen after therapy with pituitary growth hormone.
Treatment of GH deficient adults with GENOTROPIN increases serum IGF-I to normal levels, improves body composition and Quality of Life.
In addition, the following actions have been demonstrated for GENOTROPIN and/or pituitary growth hormone:
Skeletal Growth: GENOTROPIN stimulates skeletal growth in children with GHD. The measurable increase in body length after administration of either GENOTROPIN or pituitary growth hormone results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are generally low in the serum of GHD children but tend to increase during treatment with GENOTROPIN. Elevations in mean serum alkaline phosphatase concentration are also seen.
Cell Growth: It has been shown that there are fewer skeletal muscle cells in short statured children who lack endogenous growth hormone as compared with normal children. Treatment with Somatropin for Injection results in an increase in both the number and size of muscle cells.
Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with pituitary growth hormone. Treatment with GENOTROPIN results in a similar decrease in serum urea nitrogen. In adults with GHD, treatment with GENOTROPIN increases protein synthesis and increases overall lean body mass.
Children with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with GENOTROPIN. Large doses of human growth hormone may impair glucose tolerance.
In GHD patients, administration of recombinant somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.
Mineral and Bone Marker Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus. Retention of sodium, potassium, and phosphorus is induced by pituitary growth hormone in children. In treated adults, osteocalcin and procollagen levels are significantly increased. Serum concentrations of inorganic phosphate are increased in patients with GHD after therapy with GENOTROPIN or pituitary growth hormone. Serum calcium is not significantly altered by either GENOTROPIN or pituitary growth hormone. Growth hormone could increase calciuria.
Quality of Life
Quality of Life as measured by the Nottingham Health Profile showed significant improvements in “energy” and “sleep” in the GH-treated group in comparison with the placebo group. The total well-being score, produced by the Psychological General Well-Being Scale, was significantly better for the GH-group than for the placebo group. For “anxiety”, “depression” and “positive well-being” a trend towards improvement was found in the GH treated group but the effect was not statistically significant.
There is no apparent difference in the positive growth response to GENOTROPIN administered by either the IM or SC route when the frequency of dosing is the same.
When the relative bioavailability was compared with the reference (Kabi-Vial 4 IU) at a common dose of 0.1 IU/kg, both MiniQuick formulations (0.4 mg and 2.0 mg) met the standards for bioequivalence as stated in the Canadian guidance document, Comparative Bioavailability Standards: Formulations Used for Systemic Effects.
The pharmacokinetic profile after an intramuscular injection (IM) is similar to SC injection. No significant differences have been noted in Tmax, Cmax or area under the curve between these two routes of administration.
Approximately 80% of GENOTROPIN is absorbed following subcutaneous (SC) injection. Maximum serum concentrations are achieved 3 - 4 hours following SC injection.