CLINICAL PHARMACOLOGY
Mechanism of Action
Somatropin (as well as endogenous GH) binds to a dimeric GH receptor in the cell membrane of target 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
The primary and most intensively studied action of somatropin is the stimulation of linear growth. This effect is demonstrated in children with GHD and children who have PWS, were born SGA, have TS or have ISS.
Skeletal Growth
The measurable increase in bone length after administration of somatropin results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of sulfate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGFs). The somatomedins, among them IGF-1, are polypeptide hormones which are synthesized in the liver, kidney, and various other tissues. IGF-1 levels are low in the serum of hypopituitary dwarfs and hypophysectomized humans or animals, and increase after treatment with somatropin.
Cell Growth
It has been shown that the total number of skeletal muscle cells is markedly decreased in children with short stature lacking endogenous GH compared with normal children, and that treatment with somatropin results in an increase in both the number and size of muscle cells.
Organ Growth
Somatropin influences the size of internal organs, and it also increases red cell mass.
Protein Metabolism
Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are reflected by nitrogen retention which can be quantitated by observing the decline in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin therapy.
Carbohydrate Metabolism
Hypopituitary children sometimes experience fasting hypoglycemia that may be improved by treatment with somatropin. In healthy subjects, large doses of somatropin may impair glucose tolerance. Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as somatropin levels increase. Administration of human growth hormone to normal adults and patients with growth hormone deficiency results in increases in mean serum fasting and postprandial insulin levels, although mean values remain in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remain in the normal range.
Lipid Metabolism
Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in plasma free fatty acids and triglycerides. Untreated GHD is associated with increased body fat stores, including increased abdominal visceral and subcutaneous adipose tissue. Treatment of growth hormone deficient patients with somatropin results in a general reduction of fat stores, and decreased serum levels of low density lipoprotein (LDL) cholesterol.
Mineral Metabolism
Administration of somatropin results in an increase in total body potassium and phosphorus and to a lesser extent sodium. This retention is thought to be the result of cell growth. Serum levels of phosphate increase in children with GHD after somatropin therapy due to metabolic activity associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative calcium balance, however, may occasionally occur during somatropin treatment.
Connective Tissue Metabolism
Somatropin stimulates the synthesis of chondroitin sulfate and collagen, and increases the urinary excretion of hydroxyproline.
Pharmacokinetics
There are no pharmacokinetic studies using Omnitrope® Cartridges in patients with growth hormone deficiency.
Absorption
Following a subcutaneous injection of single dose of 5 mg Omnitrope® 5 mg/1.5 mL Cartridge or 5 mg Omnitrope® 10 mg/1.5 mL Cartridge in healthy male and female adults, the peak concentration (Cmax) was 72-74 mcg/L. The time to reach Cmax (tmax) for Omnitrope was 4.0 hours.
The aqueous formulations of 5 mg/1.5 mL Omnitrope® cartridge and 10 mg/mL Omnitrope® cartridge are bioequivalent to the lyophilized 5.8 mg/vial Omnitrope® formulation.
Metabolism
Somatropin is metabolized in both the liver and kidneys by proteolytic degradation. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation.
Excretion
The mean terminal half-life of somatropin after subcutaneous administration of Omnitrope® Cartridge in healthy adults is 2.5-2.8 hours. The mean clearance of subcutaneously administered Omnitrope® Cartridge in healthy adults was about 0.14 L/hr∙kg.
Specific Populations
Pediatric:
No pharmacokinetic studies of Omnitrope® have been conducted in pediatric patients.
Gender:
The effect of gender on pharmacokinetics of Omnitrope® has not been evaluated in pediatric patients.
Race:
No studies have been conducted with Omnitrope® to assess pharmacokinetic differences among races.
Renal or hepatic impairment:
No pharmacokinetic studies have been conducted with Omnitrope® in patients with renal or hepatic impairment.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and fertility studies have not been conducted with Omnitrope® See Use
In
Specific Populations (8.1) for effect on fertility.
|
CLINICAL STUDIES
Pediatric Growth Hormone Deficiency (GHD)
The efficacy and safety of Omnitrope® were compared with another somatropin product approved for growth hormone deficiency (GHD) in pediatric patients. In sequential clinical trials involving a total of 89 GHD children, 44 patients received Omnitrope® for Injection (lyophilized powder) 5.8 mg/vial and 45 patients received the comparator somatropin product for 9 months. After 9 months of treatment patients who had received the comparator somatropin product were switched to Omnitrope® Cartridge (liquid) 5 mg/1.5 mL. After 15 months of treatment, all patients were switched to Omnitrope® Cartridge 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 Omnitrope® for Injection and the comparator somatropin product during the initial 9 months of treatment.
The efficacy results after 9 months of treatment (Omnitrope® for Injection vs. the comparator somatropin product) and after 15 months (Omnitrope® Cartridge) are summarized in Table 5.
Table 5. Baseline Growth Characteristics and Effect of Omnitrope® after 9 and 15 Months of Treatment
|
Treatment Duration
|
Treatment
Group
|
Treatment
Group
|
|
0 - 9 months
|
Omnitrope
®
for Injection
(n=44)
|
Another
Somatropin
Product
(n=45)
|
|
9 - 15 months
|
Omnitrope
®
for Injection
(n=42)
|
Omnitrope
®
Cartridge
(n=44)
|
|
Treatment Parameter
|
Mean (SD)
|
Mean (SD)
|
|
Height velocity (cm/
yr
)
|
|
|
|
Pre-treatment
|
3.8 (1.2)
|
4.0 (0.8)
|
|
Month 9
|
10.7 (2.6)
|
10.7 (2.9)
|
|
Month 15
|
8.5 (1.8)
|
8.6 (2.0)
|
|
Height velocity SDS
|
|
|
|
Pre-treatment
|
-2.4 (1.3)
|
-2.3 (1.1)
|
|
Month 9
|
6.1 (3.7)
|
5.4 (3.2)
|
|
Month 15
|
3.4 (2.6)
|
3.2 (2.9)
|
|
Height SDS
|
|
|
|
Pre-treatment
|
-3.0 (0.7)
|
-3.1 (0.9)
|
|
Month 9
|
-2.3 (0.7)
|
-2.5 (0.7)
|
|
Month 15
|
-2.0 (0.7)
|
-2.2 (0.7)
|
|
IGF-1
|
|
|
|
Pre-treatment
|
159 (92)
|
158 (43)
|
|
Month 9
|
291 (174)
|
302 (183)
|
|
Month 15
|
300 (225)
|
323 (189)
|
|
IGFBP-3
|
|
|
|
Pre-treatment
|
3.5 (1.3)
|
3.5 (1.0)
|
|
Month 9
|
4.6 (3.0)
|
4.0 (1.5)
|
|
Month 15
|
4.6 (1.3)
|
4.9 (1.4)
|
Adult Growth Hormone Deficiency (GHD)
Another somatropin product was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6-month double-blind treatment period, during which 85 patients received this other somatropin product and 87 patients received placebo, followed by an open-label treatment period in which participating patients received this other somatropin product for up to a total of 24 months. This other somatropin product was administered as a daily SC injection at a dose of 0.04 mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months.
Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving this other somatropin product as compared with the placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline values after 12 months of treatment.
Prader-Willi Syndrome (PWS)
The safety and efficacy of another somatropin product in the treatment of pediatric patients with Prader-Willi Syndrome (PWS) were evaluated in two randomized, open-label, controlled clinical trials. Patients received either this other somatropin product or no treatment for the first year of the studies, while all patients received this other somatropin product during the second year. This other somatropin product was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group received this other somatropin product at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received this other somatropin product at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.36 mg/kg/week.
Patients who received this other somatropin product showed significant increases in linear growth during the first year of study, compared with patients who received no treatment (see
Table 6). Linear growth continued to increase in the second year, when both groups received treatment with this other somatropin product.
Table 6. Efficacy of Another Somatropin Product in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
|
Study 1
|
Study 2
|
|
Another
Somatropin
Product
(0.24
mg/kg/week)
(n=15)
|
Untreated
Control
(n=12)
|
Another
Somatropin
Product
(0.36
mg/kg/week)
(n=7)
|
Untreated
Control
(n=9)
|
|
Linear growth (cm)
Baseline height
|
112.7 ± 14.9
|
109.5 ± 12.0
|
120.3 ± 17.5
|
120.5 ± 11.2
|
|
Growth from months 0 to 12
|
11.6
± 2.3
|
5.0 ± 1.2
|
10.7 ± 2.3
|
4.3 ± 1.5
|
|
Baseline SDS
|
-1.6 ± 1.3
|
-1.8 ± 1.5
|
-2.6 ± 1.7
|
-2.1 ± 1.4
|
|
SDS at 12 months
|
-0.5
± 1.3
|
-1.9 ± 1.4
|
-1.4 ± 1.5
|
-2.2 ± 1.4
|
Changes in body composition were also observed in the patients receiving this other somatropin product (see
Table 7). These changes included a decrease in the amount of fat mass, and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while changes in body weight were similar to those seen in patients who received no treatment. Treatment with this other somatropin product did not accelerate bone age, compared with patients who received no treatment.
Table 7. Effect of Another Somatropin Product on Body Composition in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
|
Another
Somatropin
Product
(n=14)
|
Untreated
Control
(n=10)
|
|
Fat mass (kg)
Baseline
|
12.3 ± 6.8
|
9.4 ± 4.9
|
|
Change from months 0 to 12
|
-0.9
± 2.2
|
2.3 ± 2.4
|
|
Lean body mass (kg)
Baseline
|
15.6 ± 5.7
|
14.3 ± 4.0
|
|
Change from months 0 to 12
|
4.7 ± 1.9
|
0.7 ± 2.4
|
|
Lean body mass/Fat mass
Baseline
|
1.4 ± 0.4
|
1.8 ± 0.8
|
|
Change from months 0 to 12
|
1.0 ± 1.4
|
-0.1 ± 0.6
|
|
Body weight (kg)
Baseline
|
27.2 ± 12.0
|
23.2 ± 7.0
|
|
Change from months 0 to 12
|
3.7
± 2.0
|
3.5 ± 1.9
|
Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2
The safety and efficacy of another somatropin product in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either this other somatropin product (two doses per study, most often 0.24 and 0.48 mg/kg/week) as a daily SC injection or no treatment for the first 24 months of the studies. After 24 months in the studies, all patients received this other somatropin product.
Patients who received any dose of this other somatropin product showed significant increases in growth during the first 24 months of study, compared with patients who received no treatment (see
Table 8). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth between months 24 to 72 (data not shown).
Table 8. Efficacy of Another Somatropin Product in Children Born Small for Gestational Age (Mean ± SD)
|
Another
Somatropin
Product
(0.24 mg/kg/week)
(n=76)
|
Another
Somatropin
Product
(0.48 mg/kg/week)
(n=93)
|
Untreated
Control
(n=40)
|
|
Height Standard Deviation Score (SDS)
|
|
|
|
|
Baseline SDS
|
-3.2 ± 0.8
|
-3.4 ± 1.0
|
-3.1 ± 0.9
|
|
SDS at 24 months
|
-2.0 ± 0.8
|
-1.7 ± 1.0
|
-2.9 ± 0.9
|
|
Change in SDS from baseline to month 24
|
1.2
± 0.5
|
1.7
,
± 0.6
|
0.1 ± 0.3
|
Idiopathic Short Stature (ISS)
The long-term efficacy and safety of another somatropin product in patients with idiopathic short stature (ISS) were evaluated in one randomized, open-label, clinical trial that enrolled 177 children. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status (criteria for idiopathic short stature were retrospectively applied and included 126 patients). All patients were observed for height progression for 12 months and were subsequently randomized to this other somatropin product or observation only and followed to final height. Two somatropin doses were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD): chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 9. Therapy with this other somatropin product improved final height in ISS children relative to untreated controls. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to untreated control subjects. A height gain of 1 SDS was observed in 10 % of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects receiving 0.47 mg/kg/week.
Table 9. Final height SDS results for pre-pubertal patients with ISS
|
Untreated
(n=30)
|
Another
Somatropin
Product
0.033
mg/kg/day
(n=30)
|
Another
Somatropin
Product
0.067
mg/kg/day
(n=42)
|
Another
Somatropin
Product
0.033 vs.
Untreated
(95% CI)
|
Another
Somatropin
Product
0.067 vs.
Untreated
(95% CI)
|
| Least square means based on ANCOVA (final height SDS and final height SDS minus baseline predicted height SDS were adjusted for baseline height SDS) |
|
Baseline height
SDS
Final height SDS
minus Baseline
|
0.41
(0.58)
|
0.95 (0.75)
|
1.36 (0.64)
|
+0.53 (0.20, 0.87)
p=0.0022
|
+0.94 (0.63, 1.26)
p<0.0001
|
|
Baseline
predicted ht
Final height SDS
minus baseline
predicted final
height SDS
|
0.23 (0.66)
|
0.73 (0.63)
|
1.05 (0.83)
|
+0.60 (0.09, 1.11)
p=0.0217
|
+0.90 (0.42, 1.39)
p=0.0004
|
Turner Syndrome
Two randomized, open-label, clinical trials were conducted that evaluated the efficacy and safety of another somatropin product in Turner syndrome patients with short stature. Turner syndrome patients were treated with this other somatropin product alone or this other somatropin product plus adjunctive hormonal therapy (ethinylestradiol or oxandrolone). A total of 38 patients were treated with this other somatropin product alone in the two studies. In Study 1, 22 patients were treated for 12 months, and in Study 2, 16 patients were treated for 12 months. Patients received this other somatropin product at a dose between 0.13 to 0.33 mg/kg/week.
SDS for height velocity and height are expressed using either the Tanner (Study 1) or Sempé (Study 2) standards for age-matched normal children as well as the Ranke standard (both studies) for age-matched, untreated Turner syndrome patients. As seen in Table 10, height velocity SDS and height SDS values were smaller at baseline and after treatment with this other somatropin product when the normative standards were utilized as opposed to the Turner syndrome standard.
Both studies demonstrated statistically significant increases from baseline in all of the linear growth variables (i.e., mean height velocity, height velocity SDS, and height SDS) after treatment with this other somatropin product (see
Table 10). The linear growth response was greater in Study 1 wherein patients were treated with a larger dose of this other somatropin product.
Table 10. Growth Parameters (mean ± SD) after 12 Months of Treatment with Another Somatropin Product in Pediatric Patients with Turner Syndrome in Two Open Label Studies
|
Another
somatropin
product
0.33 mg/kg/week
Study 1* n=22
|
Another
somatropin
product
0.13-0.23 mg/kg/week
Study 2† n=16
|
SDS = Standard Deviation Score
Ranke standard based on age-matched, untreated Turner syndrome patients
Tanner*/Sempé† standards based on age-matched normal children
p<0.05, for all changes from baseline |
|
Height Velocity (cm/yr)
|
|
|
|
Baseline
|
4.1 ± 1.5
|
3.9 ± 1.0
|
|
Month 12
|
7.8 ± 1.6
|
6.1 ± 0.9
|
|
Change from baseline (95% CI)
|
3.7 (3.0, 4.3)
|
2.2 (1.5, 2.9)
|
|
Height Velocity SDS
(Tanner*/Sempé† Standards) (n=20)
|
|
|
|
Baseline
|
-2.3 ± 1.4
|
-1.6 ± 0.6
|
|
Month 12
|
2.2 ± 2.3
|
0.7 ± 1.3
|
|
Change from baseline (95% CI)
|
4.6 (3.5, 5.6)
|
2.2 (1.4, 3.0)
|
|
Height Velocity SDS (Ranke
Standard)
|
|
|
|
Baseline
|
-0.1 ± 1.2
|
-0.4 ± 0.6
|
|
Month 12
|
4.2 ± 1.2
|
2.3 ± 1.2
|
|
Change from baseline (95% CI)
|
4.3 (3.5, 5.0)
|
2.7 (1.8, 3.5)
|
|
Height SDS (Tanner*/Sempé†
Standards)
|
|
|
|
Baseline
|
-3.1 ± 1.0
|
-3.2 ± 1.0
|
|
Month 12
|
-2.7 ± 1.1
|
-2.9 ± 1.0
|
|
Change from baseline (95% CI)
|
0.4 (0.3, 0.6)
|
0.3 (0.1, 0.4)
|
|
Height SDS (Ranke Standard)
|
|
|
|
Baseline
|
-0.2 ± 0.8
|
-0.3 ± 0.8
|
|
Month 12
|
0.6 ± 0.9
|
0.1 ± 0.8
|
|
Change from baseline (95% CI)
|
0.8 (0.7, 0.9)
|
0.5 (0.4, 0.5)
|
|
