CLINICAL PHARMACOLOGY
Mechanism of Action
Somatropin (as well as endogenous growth hormone) binds to dimeric growth hormone receptors located within the cell membranes of target tissue cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Some of these pharmacodynamic effects are primarily mediated by IGF-1 produced in the liver and also locally (e.g., skeletal growth, protein synthesis), while others are primarily a consequence of the direct effects of somatropin (e.g., lipolysis) [see Pharmacodynamics].
Pharmacodynamics
Tissue Growth
Skeletal Growth: Saizen® stimulates skeletal growth in prepubertal children with pituitary growth hormone deficiency. Skeletal growth is accomplished at the epiphyseal plates at the ends of long bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by growth hormone and one of its mediators, insulin-like growth factor-1. Serum levels of insulin-like growth factor-1 (IGF-1) are low in children and adolescents who are growth hormone deficient, but increase during treatment with Saizen®. Linear growth continues until the growth plates fuse at the end of puberty.
Cell Growth: Treatment with pituitary-derived human growth hormone results in an increase in both the number and the size of skeletal muscle cells.
Organ Growth: Somatropin influences the size and function of internal organs and increases red cell mass.
Protein Metabolism
Linear growth is facilitated in part by increased cellular protein synthesis. This is reflected by increased cellular uptake of amino acids and nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during somatropin therapy.
Carbohydrate Metabolism
Somatropin is a modulator of carbohydrate metabolism. Children with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia that is improved by treatment with somatropin. Saizen® therapy may decrease glucose tolerance. Administration of Saizen® to normal adults and patients with growth hormone deficiency resulted in transient increases in mean serum fasting and postprandial insulin levels. However, glucose levels remained in the normal range.
Lipid Metabolism
Acute administration of somatropin to humans results in lipid mobilization. Nonesterified fatty acids increase in plasma within one hour of Saizen® administration. In growth hormone deficient patients, long-term somatropin administration often decreases body fat. Mean cholesterol levels decreased in patients treated with Saizen®. The clinical significance of this decrease in cholesterol level is unknown.
Mineral Metabolism
Somatropin administration results in the retention of total body potassium, phosphorus, and sodium. Serum calcium levels appear to be unaffected.
Connective Tissue/Bone Metabolism
Somatropin stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.
Pharmacokinetics
Absorption - The absolute bioavailability of somatropin after subcutaneous administration ranges between 70 to 90%.
Distribution - The steady-state volume of distribution (mean ±SD) of somatropin following intravenous administration in healthy volunteers was estimated to be 12.0 ± 1.08 L.
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 is returned to the systemic circulation. The mean half-life of intravenous somatropin in normal males is around 0.6 hours, whereas subcutaneously and intramuscularly administered somatropin has a half-life of around 2 hours. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site.
Excretion - The clearance (mean ±SD) of intravenously administered somatropin in six normal male volunteers was 14.6 ± 2.8 L/hr.
Specific Populations
Pediatric - The pharmacokinetics of somatropin is similar in children and adults. However, no pharmacokinetic studies of Saizen® have been conducted in pediatric patients.
Gender - No gender studies have been performed in children for somatropin. In adults, the clearance of somatropin in both men and women tends to be similar. However, no studies have been conducted to evaluate the effect of gender on pharmacokinetics of Saizen®
.
Race - No studies have been conducted to determine the effect of race on the pharmacokinetics of Saizen®.
Renal Impairment- Children and adults with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Saizen®.
Hepatic Impairment - A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies for carcinogenicity have not been performed with Saizen®. There is no evidence from animal studies to date of Saizen®-induced mutagenicity or impairment of fertility.
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