SciTropin A Mechanism of Action

Pharmacotherapeutic Group: Pituitary and hypothalamic hormones and analogues, anterior pituitary lobe hormones and analogues. ATC Code: H01AC01.
Pharmacology: Pharmacodynamics: Somatropin is a potent metabolic hormone of importance for the metabolism of lipids, carbohydrates and proteins. In children with inadequate endogenous growth hormone, somatropin stimulates linear growth and increases growth rate. In adults as well as in children, somatropin maintains a normal body composition by increasing nitrogen retention and stimulation of skeletal muscle growth, and by mobilization of body fat. Visceral adipose tissue is particularly responsive to somatropin. In addition to enhanced lipolysis, somatropin decreases the uptake of triglycerides into body fat stores.
Serum concentrations of IGF-I (Insulin-like Growth Factor-I) and IGFBP3 (Insulin-like Growth Factor Binding Protein 3) are increased by somatropin. In addition, the following actions have been demonstrated.
Lipid metabolism: Somatropin induces hepatic LDL cholesterol receptors, and affects the profile of serum lipids and lipoproteins. In general, administration of somatropin to growth hormone deficient patients results in reduction in serum LDL and apolipoprotein B. A reduction in serum total cholesterol may also be observed.
Carbohydrate metabolism: Somatropin increases insulin but fasting blood glucose is commonly unchanged. Children with hypopituitarism may experience fasting hypoglycaemia. This condition is reversed by somatropin.
Water and mineral metabolism: Growth hormone deficiency is associated with decreased plasma and extracellular volumes. Both are rapidly increased after treatment with somatropin. Somatropin induces the retention of sodium, potassium and phosphorous.
Bone metabolism: Somatropin stimulates the turnover of skeletal bone. Long-term administration of somatropin to growth hormone deficient patients with osteopenia results in an increase in bone mineral content and density at weight-bearing sites.
Physical capacity: Muscle strength and physical exercise capacity are improved after long-term treatment with somatropin. Somatropin also increases cardiac output, but the mechanism has yet to be clarified. A decrease in peripheral vascular resistance may contribute to this effect.
In clinical trials in short children born SGA doses of 0.033 and 0.067 mg/kg body weight per day have been used for treatment until final height. In 56 patients who were continuously treated and have reached (near) final height, the mean change from height at the start of treatment was +1.90 SDS (0.033 mg/kg body weight per day) and +2.19 SDS (0.067 mg/kg body weight per day). Literature data from untreated SGA children without early spontaneous catch-up suggest a late growth of 0.5 SDS.
Clinical Trial Data for the Biosimilar Describing Clinical Similarity to the Reference Product: In three sequential clinical trials, involving a total of previously untreated 89 GHD children the efficacy and safety of SciTropin A were compared with another somatropin (Genotropin) product approved for growth hormone deficiency (GHD) in pediatric patients.
44 patients received SciTropin A powder for solution for injection (p.f.s.f.i.) 5.8mg/ vial and 45 patients received Genotropin for 9 months. After 9 months of treatment patients who had received Genotropin product were switched to SciTropin A solution for injection (s.f.i.) 5 mg/1.5 mL. After 15 months of treatment, all patients were switched to SciTropin A s.f.i, to collect long-term efficacy and safety data.
In both groups, somatropin was administered as a daily subcutaneous injection at a dose of 0.03 mg/kg. Similar effects on growth were observed between SciTropin A p.f.s.f.i. and Genotropin during the initial 9 months of treatment.
The efficacy results after 9 months of treatment (SciTropin A p.f.s.f.i. vs. Genotropin and after 15 months (SciTropin A s.f.i) are summarized in Table 1. The table also shows the long-term efficacy results for both treatment groups. (See Table 1.)

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The results of three consecutive multicenter studies demonstrated equivalent therapeutic efficacy and clinical comparability between SciTropin A p.f.s.f.i. and Genotropin and between SciTropin A p.f.s.f.i. and SciTropin A s.f.i.
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.
The following events were observed during the clinical study with SciTropin A p.f.s.f.i. (See Table 2.)

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The following events were observed during the clinical studies with SciTropin A s.f.i. (See Table 3.)

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As with all protein drugs, a small percentage of patients may develop antibodies to the protein. Additional efficacy analyses carried out revealed that the presence of anti-hGH antibodies did not affect the growth parameters of the patients with a positive anti-rhGH and anti-HCP test. The safety profiles were similar and as expected from experience with established rhGH preparations.
The long-term safety of SciTropin A solution in the treatment of children with GHD was demonstrated.
Pharmacokinetics: Absorption: The bioavailability of subcutaneously administered somatropin is approximately 80% in both healthy subjects and growth hormone deficient patients. A subcutaneous dose of 5 mg of SciTropin A 5 mg/1.5 mL Solution for Injection in healthy adults results in plasma Cmax and tmax values of 72±28 µg/L and 4.0±2.0 hours, respectively. A subcutaneous dose of 5mg of SciTropin A 10 mg/1.5 mL Solution for Injection in healthy adults results in plasma Cmax and tmax values of 74±22 µg/L and 3.9±1.2 hours, respectively.
Elimination: The mean terminal half-life of somatropin after intravenous administration in growth hormone deficient adults is about 0.4 hours. However, after subcutaneous administration of SciTropin A, a half-life of 3 hours is achieved. The observed difference is likely due to slow absorption from the injection site following subcutaneous administration.
Sub-populations: The absolute bioavailability of somatropin seems to be similar in males and females following subcutaneous administration.
Information about the pharmacokinetics of somatropin in geriatric and paediatric populations, in different races and in patients with renal, hepatic or cardiac insufficiency is either lacking or incomplete.
Toxicology: Preclinical Safety Data: In studies with SciTropin A regarding subacute toxicity and local tolerance, no clinically relevant effects have been observed.
In other studies with somatropin regarding general toxicity, local tolerance and reproduction toxicity no clinically relevant effects have been observed.
With somatropins, in vitro and in vivo genotoxicity studies on gene mutations and induction of chromosome aberrations have been negative.
An increased chromosome fragility has been observed in one in vitro study on lymphocytes taken from patients after long term treatment with somatropin and following the addition of the radiomimetic medicinal product bleomycin. The clinical significance of this finding is unclear.
In another study with somatropin, no increase in chromosomal abnormalities was found in the lymphocytes of patients who had received long-term somatropin therapy.