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Accretropin

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Accretropin

CLINICAL PHARMACOLOGY

General

Linear Growth - Somatropin stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated that somatropin is therapeutically equivalent to human growth hormone of pituitary origin and achieves equivalent pharmacokinetic profiles in normal adults.

In addition, the following actions have been demonstrated for human growth hormone (somatropin and/or human growth hormone of pituitary origin).

Tissue Growth - 1. Skeletal Growth: Somatropin stimulates skeletal growth in children with growth failure due to lack of adequate secretion of endogenous GH (i.e. growth hormone deficiency), or in patients with Turner Syndrome. The measurable increase in body length after administration of human growth hormone results from an effect on the epiphysial plates of the long bones. Concentrations of IGF-1, which may play a role in skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase during treatment with somatropin. Elevations in mean serum alkaline phosphatase concentrations may also be seen. 2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in pediatric patients with short stature who lack endogenous growth hormone as compared to the normal pediatric population. Treatment with human growth hormone results in an increase in the size and number of skeletal muscle cells.

Protein Metabolism- 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 human growth hormone.

Carbohydrate Metabolism - Growth hormone is a modulator of carbohydrate metabolism. Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with somatropin. Large doses of human growth hormone may impair glucose tolerance (see PRECAUTIONS, General).

Lipid Metabolism - In growth hormone-deficient patients, administration of human growth hormone has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.

Mineral Metabolism - Retention of sodium, potassium, and phosphorus is induced by human growth hormone. Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with human growth hormone. Serum calcium is not significantly altered in patients treated with human growth hormone.

Pharmacokinetics

Absorption -Accretropin™ (somatropin injection) has been studied following subcutaneous administration in adult volunteers. Bioavailability of Accretropin™ (somatropin injection) was not determined. However, based on the bioavailability of other r-hGH products, absolute bioavailability has been estimated at approximately 70% when administered subcutaneously (Janssen et al., 1999; Zeisel et al., 1992).

Distribution - The volume of distribution of somatropin was not determined for Accretropin™ (somatropin injection) .

Metabolism - Extensive metabolism studies have not been conducted. Somatropin is metabolized in the liver and kidneys. In the kidneys, hGH is catabolized to its constitutive amino acids, which are then returned to the systemic circulation. Clearance was not determined for Accretropin™ (somatropin injection) . The mean half-life of subcutaneously administered Accretropin™ (somatropin injection) is 3.63 hours (Table 1).

Excretion - Urinary excretion of intact somatropin has not been measured.

Table 1: Summary of somatropin pharmacokinetic parameters in the normal population following a 4 mg dose of Accretropin™ (somatropin injection) administered subcutaneously*

  AUC(0-t)
(ng•h/mL)
AUC(0-inf)
(ng•h/mL)
Cmax
(ng/mL)
Tmax (h) t1/2 (h)
mean ± SD 238.09 ± 44.11 255.31 ± 43.03 29.49 ± 8.32 3.50 (2-6) 3.63 ± 1.33
*Abbreviations: AUC0-t=area under the curve until 24 hours after administration; AUC0-inf=area under the curve to infinity; Cmax=maximum concentration; t½=half-life; Tmax=time to maximum concentration (given as the median value with range); SD=standard deviation.

Special Populations

Geriatric - The pharmacokinetics of Accretropin™ (somatropin injection) have not been studied in patients greater than 65 years of age.

Pediatric - No formal pharmacokinetic studies of r-hGH in pediatric patients have been conducted using Accretropin™ (somatropin injection) .

Gender - No studies have been performed to evaluate the effect of gender on the pharmacokinetics of Accretropin™ (somatropin injection) .

Race - No data are available.

Renal, Hepatic insufficiency - No studies have been performed with Accretropin™ (somatropin injection) in patients with renal or hepatic insufficiency.

Figure 1. Mean serum hGH levels over time following single dose administration.

Mean serum hGH levels over time following single dose administration - illustration

Figure 1 shows changes in mean hGH serum concentrations over time following single dose administration of Accretropin™ (somatropin injection) (N= 20, data represent means ± Standard Error).

Clinical Trials

Pediatric Patients with GHD

The safety and efficacy of Accretropin™ (somatropin injection) in the treatment of pediatric patients with GHD was studied in a single-arm, open-label, multicenter trial conducted in 44 patients with GHD who were treated for up to 3 years with an Accretropin™ (somatropin injection) dose of 0.03 to 0.05 mg/kg/day (0.18 to 0.30 mg/kg/week) subcutaneously. The efficacy of Accretropin™ (somatropin injection) is displayed in Table 2.

Table 2: Height Velocity (cm/yr) and Height Velocity SDS in patients with GHD*

  Height Velocity (cm/yr)
N= number of patients
Mean (cm/yr) ± SD
Height Velocity SDS
N= number of patients
Mean (SDS) ± SD
Year 1 N=41
8.88 ± 2.29
N=41
3.60 ± 3.58
Year 2 N=34
7.64 ± 1.41
N=33
1.95 ± 2.32
Year 3 N=26
6.98 ± 1.62
N=26
1.76 ± 2.87
*Patients who entered puberty during the clinical trial were discontinued as per protocol specifications.

Height SD score calculated relative to population of normally growing children increased on Accretropin™ (somatropin injection) treatment from -3.04 at baseline to -2.46 at one year, -2.12 at two years, and -1.78 at three years.

Pediatric Patients with Turner Syndrome

The safety and efficacy of Accretropin™ (somatropin injection) in the treatment of children with short stature due to Turner Syndrome was evaluated in a single-arm, open-label, single-center trial conducted in 37 patients treated with an Accretropin™ (somatropin injection) dose of 0.06 mg/kg/day subcutaneously (0.36 mg/kg/week). The efficacy of Accretropin™ (somatropin injection) is shown in Table 3.

Table 3: Height Velocity (cm/yr) and Height Velocity SDS in patients with Turner Syndrome

  Height Velocity (cm/yr)
N= number of patients
Mean (cm/yr) ± SD
Height Velocity SDS
N= number of patients
Mean (SDS) ± SD
Year 1 N=37
8.56 ± 1.71
N=37
3.08 ± 2.56
Year 2 N=36
6.85 ± 1.21
N=36
1.50 ± 1.90
Year 3 N=35
5.84 ± 1.86
N=33
0.48 ± 3.28

Height SD score calculated relative to population of Turner Syndrome patients increased on Accretropin™ (somatropin injection) treatment from -3.17 at baseline to -2.67 at one year, -2.43 at two years, and -2.28 at three years.

Last reviewed on RxList: 2/8/2008
This monograph has been modified to include the generic and brand name in many instances.

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