Saizen

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.

Clinical Studies

Adult Growth Hormone Deficiency (GHD)

A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in 115 adults with growth hormone deficiency comparing the effects of Saizen® [somatropin (rDNA origin) for injection] and placebo on body composition. Patients in the active treatment arm were treated with Saizen® at an initial dose of 0.005 mg/kg/day for one month which was increased to 0.01 mg/kg/day if tolerated for the remaining five months of the study. The primary endpoint was the change from baseline in lean body mass measured by dual energy X-ray absorptiometry (DXA) after 6 months. Treatment with Saizen® produced significant (p < 0.001) increases from baseline in LBM compared to placebo (Table 2).

Table 2 : Lean Body Mass (kg) by DXA

  Saizen® (n=52) Placebo (n=51)
Baseline (mean) 47.7 54.0
Change from baseline at 6 months (mean) +1.9 -0.2
Treatment difference (mean) 2.1
95% confidence interval (1.3, 2.9)
p-value < 0.001

Sixty-seven (58%) of the 115 randomized patients were male. The adjusted mean treatment difference on the increase in lean body mass from baseline was significantly greater in males (2.9 kg) than females (0.8 kg).

Ninety-seven (84%) of the 115 randomized patients had adult onset GHD. The adjusted mean treatment differences on the increase in lean body mass from baseline were not significantly different in AO GHD (2.1 kg) compared with childhood onset GHD (1.0 kg) patients. However, there were relatively few patients with childhood onset GHD (n=18) on which to base the comparison.

Analysis of the treatment difference on the change from baseline in total fat mass (by DXA) revealed a significant decrease (p < 0.001) in the Saizen®-treated group compared to the placebo group. Saizen® also produced beneficial effects on several bone turnover markers including bone specific alkaline phosphatase, C-terminal propeptide, osteocalcin, urine deoxypyridinoline and iPTH.

One hundred and eleven patients were enrolled in an open label follow up study and treated with Saizen® for an additional 6-30 months. During this period, the beneficial effects on lean body mass and total fat mass achieved during the initial six months of treatment were maintained.

Last reviewed on RxList: 6/27/2014
This monograph has been modified to include the generic and brand name in many instances.

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