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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 reductions 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 hypoglycemia. 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 phosphorus.
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.
Pharmacokinetics: Absorption: The bioavailability of subcutaneously administered somatropin is approximately 80% in both healthy subjects and growth hormone deficient patients. Results were comparable in both male and female patients. A subcutaneous dose of 0.035 mg/kg of somatropin results in plasma Cmax and tmax values in the range of 13-35 ng/mL and 3-6 hours, respectively.
In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL somatropin was 35% greater than that for 1.3 mg/mL somatropin. The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL, respectively.
In a similar study involving pediatric GHD patients, 5.3 mg/mL somatropin yielded a mean AUC that was 17% greater than that for 1.3 mg/mL somatropin. The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.
Adult GHD patients received two single SC doses of 0.03 mg/kg of somatropin at a concentration of 1.3 mg/mL, with a one- to four-week washout period between injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.
There are no data on the bioequivalence between the 12-mg/mL formulation and either the 1.3-mg/mL or the 5.3-mg/mL formulations.
Distribution: The mean volume of distribution of somatropin following administration to GHD adults was estimated to be 1.3 (± 0.8) L/kg.
Metabolism: The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. The mean terminal half-life of intravenous somatropin in normal adults is 0.4 hours, whereas subcutaneously administered somatropin has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.
Excretion: The mean clearance of subcutaneously administered somatropin in 16 GHD adult patients was 0.3 (± 0.11) L/h/kg.
Special Populations: Pediatric: The pharmacokinetics of somatropin are similar in GHD pediatric and adult patients.
Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of somatropin was similar in males and females.
Race: No studies have been conducted with somatropin to assess pharmacokinetic differences among races.
Renal, hepatic, or cardiac insufficiency: Information about the pharmacokinetics of somatropin in patients with renal, hepatic, or cardiac insufficiency is either lacking or incomplete.
Toxicology: Preclinical safety data: In studies regarding general toxicity, local tolerance and reproduction toxicity, no clinically relevant effects have been observed.
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 drug bleomycin. The clinical significance of this finding is unclear.
In another study, no increase in chromosomal abnormalities was found in the lymphocytes of patients who had received long-term somatropin therapy.
