In vivo preclinical and clinical testing has demonstrated that growth
hormone (GH) stimulates longitudinal bone growth and elevates insulin-like growth
factor-I (IGF-I) levels.
Actions that have been demonstrated for hGH include:
- Tissue Growth - 1) Skeletal Growth: GH stimulates skeletal growth
in pediatric patients with growth failure due to a lack of adequate secretion
of endogenous GH. Skeletal growth is accomplished at the epiphyseal plates
at the ends of a growing bone. Growth and metabolism of epiphyseal plate cells
are directly stimulated by GH and one of its mediators, IGF-I. Serum levels
of IGF-I are low in children and adolescents who are growth hormone deficient
(GHD), but increase during treatment with GH. In pediatric patients, new bone
is formed at the epiphyses in response to GH and IGF-I. This results in linear
growth until these growth plates fuse at the end of puberty. 2) Cell Growth:
Treatment with hGH results in an increase in both the number and the size
of skeletal muscle cells. 3) Organ Growth: GH increases the size of internal
organs, including kidneys, and increases red cell mass. Treatment of hypophysectomized
or genetic dwarf rats with GH results in increases in organ and overall body
growth. In normal rats subjected to nephrectomy-induced uremia, GH promoted
skeletal and body growth.
- Protein Metabolism - Linear growth is facilitated in part by GH-stimulated
protein synthesis. This is reflected by nitrogen retention as demonstrated
by a decline in urinary nitrogen excretion and blood urea nitrogen during
- Carbohydrate Metabolism - GH is a modulator of carbohydrate metabolism.
Patients with inadequate endogenous secretion of GH sometimes experience fasting
hypoglycemia that is improved by treatment with GH. GH therapy may decrease
insulin sensitivity. Administration of hGH formulated for daily dosing resulted
in increased mean fasting and postprandial insulin levels, more commonly in
overweight or obese individuals. Mean trough levels for fasting and postprandial
insulin were unchanged after 3 or 6 months of Nutropin Depot (somatropin (rdna origin) for inj) therapy in GHD
children. As with daily GH, mean trough levels for fasting glucose, postprandial
glucose, and hemoglobin A1c remained unchanged after 3 or 6 months
of Nutropin Depot (somatropin (rdna origin) for inj) therapy.
- Lipid Metabolism - In GHD patients, administration of GH formulated
for daily dosing resulted in lipid mobilization, reduction in body fat stores,
increased plasma fatty acids, and decreased plasma cholesterol levels.
- Mineral Metabolism - The retention of total body potassium in response
to GH administration apparently results from cellular growth. Serum levels
of inorganic phosphorus may increase slightly in patients with inadequate
secretion of endogenous GH due to metabolic activity associated with bone
growth as well as increased tubular reabsorption of phosphate by the kidney.
Serum calcium is not significantly altered in these patients. Sodium retention
also occurs. (See PRECAUTIONS: Laboratory Tests.)
GH therapy results in increases in serum alkaline phosphatase.
- Connective Tissue Metabolism - GH stimulates the synthesis of chondroitin
sulfate and collagen as well as the urinary excretion of hydroxyproline.
Nutropin Depot (somatropin (rdna origin) for inj) is a long-acting dosage form of somatropin designed to be administered by subcutaneous (SC) injection once or twice monthly. Following the injection, bioactive rhGH is released from the microspheres into the SC environment initially by diffusion, followed by both polymer degradation and diffusion. Although no studies have been performed that address the distribution, elimination, or metabolism of Nutropin Depot (somatropin (rdna origin) for inj) , once released and absorbed the rhGH is believed to be distributed and eliminated in a manner similar to somatropin formulated for daily administration.
The serum hGH concentration-time profiles of single doses of 0.75 mg/kg and
1.5 mg/kg of Nutropin Depot (somatropin (rdna origin) for inj) have been characterized in pediatric GHD patients
(refer to Figure 1). The in vivo profiles are characterized by an initial
rapid release followed by a slow decline in GH concentration. Both the maximum
concentrations achieved (Cmax) and total exposure (AUC0-28 days)
appear to be proportional to dose. Serum hGH levels greater than 1 Âµg/L persist
for approximately 11-14 days postdose for the two doses. Repeated dosing of
Nutropin Depot (somatropin (rdna origin) for inj) over 6 months showed no progressive accumulation of GH.
Absorption - In a study of Nutropin Depot (somatropin (rdna origin) for inj) in pediatric patients
with GHD, an SC dose of 0.75 mg/kg (n = 12) or 1.5 mg/kg (n = 8) was administered.
The mean ± SD hGH Cmax values were 48±26 Âµg/L and 90±23
Âµg/L, respectively, at 12-13 hours postdose. The corresponding AUC0-28
days values were 83±49 Âµg • day/L and 140±34 Âµg•day/L,
respectively, for the two doses. For the 0.75 mg/kg and 1.5 mg/kg doses, the
AUC0-2days accounted for approximately 52±16 percent and 61±10
percent of the total AUC0-28 days, respectively. Estimates of relative
bioavailability in GHD children for a single dose of Nutropin Depot (somatropin (rdna origin) for inj) ranged from
33% to 38% when compared to a single dose of Nutropin AQ® [somatropin (rDNA
origin) injection] in healthy adults, and from 48% to 55% when compared to chronically
dosed Protropin® (somatrem for injection) in GHD children.
Distribution - Animal studies with rhGH formulated
for daily administration showed that GH localizes to highly perfused organs,
particularly the liver and kidney. The volume of distribution at steady state
for rhGH formulated for daily administration in healthy adult males is about
50 mL/kg body weight, approximating the serum volume.
Metabolism - Both the liver and kidney have been
shown to be important metabolizing organs for GH. Animal studies using rhGH
formulated for daily administration suggest that the kidney is the dominant
organ of clearance. GH is filtered at the glomerulus and reabsorbed in the proximal
tubules. It is then cleaved within renal cells into its constituent amino acids,
which return to the systemic circulation.
Elimination - The mean terminal t1/2
after intravenous (IV) administration of rhGH formulated for daily administration
in healthy adult males is estimated to be 19.5+3.1 minutes. Clearance of rhGH
after IV administration in healthy adults and children is reported to be in
the range of 116-174 mL/hr/kg.
Figure 1: Single-Dose Mean (SD) GH Concentrations in Pediatric
Pediatric - Available literature data suggest that rhGH clearances
are similar in adults and children.
Gender - Following administration of either 0.75 mg/kg or 1.5
mg/kg Nutropin Depot (somatropin (rdna origin) for inj) , Day 1 GH levels were higher in females compared to males.
No relationship was observed between gender and pharmacodynamic marker (IGF-I
and IGFBP-3) levels.
Race - The effect of race on Nutropin Depot (somatropin (rdna origin) for inj) disposition is unknown
due to the limited number of non-Caucasian patients in the Nutropin Depot (somatropin (rdna origin) for inj) studies.
Growth Hormone Deficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied
in healthy adults or children. However, reported values for clearance of rhGH
formulated for daily administration in adults and children with GHD range from
138-245 mL/hr/kg and are similar to those observed in healthy adults and children.
Mean terminal t1/2 values following IV and SC administration in adult
and pediatric patients with GHD are also similar to those observed in healthy
Renal Insufficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in
patients with renal insufficiency. Children and adults with chronic renal failure
(CRF) and end-stage renal disease (ESRD) tend to have decreased clearance of
rhGH formulated for daily administration compared with normals. Endogenous GH
production may also increase in some individuals with ESRD. However, no GH accumulation
has been reported in children with CRF or ESRD dosed with daily regimens.
Hepatic Insufficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in
patients with hepatic insufficiency. A reduction in clearance of rhGH formulated
for daily administration has been noted in patients with severe liver dysfunction.
The clinical significance of this decrease is unknown.
IGF-I levels peaked between 1.5 and 3.5 days postdose and remained above baseline for approximately 16 to 20 days, confirming GH activity for an extended period. Repeated dosing of Nutropin Depot (somatropin (rdna origin) for inj) over 6 months showed no progressive accumulation of IGF-I (as shown in Figure 2) or IGF-binding protein 3 (IGFBP-3).
Figure 2: Repeated-Dose Mean (SD) IGF-I Concentrations in
Pediatric GHD Patients
Pediatric Growth Hormone Deficiency (GHD)
In two multicenter, open-label clinical studies in prepubertal children (mean
age (± SD) 7.4+2.8) with idiopathic or organic GHD previously untreated
with rhGH, 91 patients were treated with Nutropin Depot (somatropin (rdna origin) for inj) at 1.5 mg/kg once monthly
or 0.75 mg/kg twice monthly by subcutaneous injection for up to six months.
(See DOSAGE AND ADMINISTRATION for the number
of injections required per dose.) The mean prestudy growth rate was 4.8±2.4
cm/yr (n=89). The dose-pooled, mean 6-month annualized growth rate on Nutropin
Depot therapy was 8.4±2.2 cm/yr (n=89).
Seventy-six patients continued treatment in an extension study. For patients
who completed 12 months the mean growth rate was 7.8±1.9 cm/yr for the
two dose groups combined (n=69). Mean height SD score changed from -3.0±1.0
prestudy to -2.5±0.9 at Month 12 (n=69). The mean 0 to 12 month change
in bone age was 1.0±0.4 years (n=63). During the long-term extension
study, fourteen of seventy-five (19%) patients discontinued due to dissatisfaction
with growth response. Historical studies of GHD children treated with daily
Protropin® (somatrem for injection) or Nutropin® [somatropin (rDNA origin)
for injection] injections for 12 months at 0.3 mg/kg weekly had the following
mean values: baseline growth rate 3.6 to 4.8 cm/yr; first year growth rate 10.1
to 11.3 cm/yr; first year change in bone age 1.1 to 1.5 years.
In a dose-ranging study, 24 patients previously treated with daily GH (mean
age 9.6±2.2 years; mean duration of prior GH therapy 2.8±1.6 yr,
range 0.9 to 6.1 yr) were switched to Nutropin Depot (somatropin (rdna origin) for inj) therapy at the above doses.
The mean growth rate on previous treatment was 8.2±3.0 cm/yr (range 3.2
to 13.1 cm/yr) and on Nutropin Depot (somatropin (rdna origin) for inj) was 5.1±2.0 cm/yr (range 2.4 to
9.6 cm/yr). During a long-term extension study, four of ten previously treated
patients discontinued due to dissatisfaction with growth response. Historical
studies of GHD children (n=181) treated with daily Protropin or Nutropin at
a dose of 0.3 mg/kg weekly had the following mean growth rates: first year growth
rate 9.7 to 11.4 cm/yr; second year growth rate 8.1 to 8.9 cm/yr; third
year growth rate 7.5 to 7.8 cm/yr; fourth year growth rate 6.6 to 7.1 cm/yr.