Nutropin Description
Nutropin Depot [somatropin (rDNA origin) for injection] is a human growth hormone (hGH) produced by recombinant DNA technology. Nutropin has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of pituitary‑derived human growth hormone. The protein is synthesized by a specific laboratory strain of E. coli as a precursor consisting of the rhGH molecule preceded by the secretion signal from an E. coli protein. This precursor is directed to the plasma membrane of the cell. The signal sequence is removed and the native protein is secreted into the periplasm so that the protein is folded appropriately as it is synthesized.
Nutropin Depot is a highly purified preparation. Biological potency is determined using a cell proliferation bioassay.
Nutropin Depot is a sterile, white, lyophilized powder intended for subcutaneous administration after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). The reconstituted product is nearly isotonic at a concentration of 5 mg/mL growth hormone (GH) and has a pH of approximately 7.4.
Each 5 mg Nutropin Depot vial contains 5 mg (approximately 15 IU) somatropin, lyophilized with 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg sodium phosphate monobasic and 1.3 mg sodium phosphate dibasic), and 1.7 mg glycine.
Each 10 mg Nutropin Depot vial contains 10 mg (approximately 30 IU) somatropin, lyophilized with 90 mg mannitol, 3.4 mg sodium phosphates (0.8 mg sodium phosphate monobasic and 2.6 mg sodium phosphate dibasic), and 3.4 mg glycine.
Bacteriostatic Water for Injection, USP is sterile water containing 0.9 percent benzyl alcohol per mL as an antimicrobial preservative packaged in a multidose vial. The diluent pH is 4.5–7.0.
Nutropin Depot – Clinical Pharmacology
General
In vitro and in vivo preclinical and clinical testing have demonstrated that Nutropin is therapeutically equivalent to pituitary‑derived human GH (HGH). Pediatric patients who lack adequate endogenous GH secretion, patients with chronic renal insufficiency, and patients with Turner syndrome that were treated with Nutropin resulted in an increase in growth rate and an increase in insulin‑like growth factor‑I (IGF‑I) levels similar to that seen with pituitary‑derived hGH.
Actions that have been demonstrated for Nutropin Depot, somatrem, and/or pituitary‑derived hGH include:
A. 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 or secondary to chronic renal insufficiency and in patients with Turner syndrome. 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 GH deficient, 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 influences the size of internal organs, including kidneys, and increases red cell mass. Treatment of hypophysectomized or genetic dwarf rats with GH results in organ growth that is proportional to the overall body growth. In normal rats subjected to nephrectomy‑induced uremia, GH promoted skeletal and body growth.
B. 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 GH therapy.
C. Carbohydrate Metabolism
GH is a modulator of carbohydrate metabolism. For example, patients with inadequate secretion of GH sometimes experience fasting hypoglycemia that is improved by treatment with GH. GH therapy may decrease insulin sensitivity. Untreated patients with chronic renal insufficiency and Turner syndrome have an increased incidence of glucose intolerance. Administration of hGH to adults or children resulted in increases in serum fasting and postprandial insulin levels, more commonly in overweight or obese individuals. In addition, mean fasting and postprandial glucose and hemoglobin A1c levels remained in the normal range.
D. Lipid Metabolism
In GH‑deficient patients, administration of GH resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels.
E. 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, chronic renal insufficiency, or patients with Turner syndrome during GH therapy 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. Adults with childhood‑onset GH deficiency show low bone mineral density (BMD). GH therapy results in increases in serum alkaline phosphatase. (See PRECAUTIONS: Laboratory Tests.)
F. Connective Tissue Metabolism
GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.
Pharmacokinetics For Nutropin Depot
Subcutaneous Absorption
The absolute bioavailability of recombinant human growth hormone (rhGH) after subcutaneous administration in healthy adult males has been determined to be 81±20%. The mean terminal t½ after subcutaneous administration is significantly longer than that seen after intravenous administration (2.1±0.43 hours vs. 19.5±3.1 minutes) indicating that the subcutaneous absorption of the compound is slow and rate‑limiting.
Distribution
Animal studies with rhGH showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for rhGH 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 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 t½ after intravenous administration of rhGH in healthy adult males is estimated to be 19.5±3.1 minutes. Clearance of rhGH after intravenous administration in healthy adults and children is reported to be in the range of 116–174 mL/hr/kg.
Bioequivalence of Formulations
Nutropin has been determined to be bioequivalent to Nutropin AQ® [somatropin (rDNA origin) injection] based on the statistical evaluation of AUC and Cmax.
SPECIAL POPULATIONS
Pediatric
Available literature data suggest that rhGH clearances are similar in adults and children.
Gender
No data are available for exogenously administered rhGH. Available data for methionyl recombinant GH, pituitary‑derived GH, and endogenous GH suggest no consistent gender‑based differences in GH clearance.
Geriatrics
Limited published data suggest that the plasma clearance and average steady‑state plasma concentration of rhGH may not be different between young and elderly patients.
Race
Reported values for half‑lives for endogenous GH in normal adult black males are not different from observed values for normal adult white males. No data for other races are available.
Growth Hormone Deficiency (GHD)
Reported values for clearance of rhGH in adults and children with GHD range 138–245 mL/hr/kg and are similar to those observed in healthy adults and children. Mean terminal t½ values following intravenous and subcutaneous administration in adult and pediatric GHD patients are also similar to those observed in healthy adult males.
Renal Insufficiency
Children and adults with chronic renal failure (CRF) and end‑stage renal disease (ESRD) tend to have decreased clearance compared to normals. In a study with six pediatric patients 7 to 11 years of age, the clearance of Nutropin was reduced by 21.5% and 22.6% after the intravenous infusion and subcutaneous injection, respectively, of 0.05 mg/kg of Nutropin compared to normal healthy adults. Endogenous GH production may also increase in some individuals with ESRD. However, no rhGH accumulation has been reported in children with CRF or ESRD dosed with current regimens.
Turner Syndrome
No pharmacokinetic data are available for exogenously administered rhGH. However, reported half‑lives, absorption, and elimination rates for endogenous GH in this population are similar to the ranges observed for normal subjects and GHD populations.
Hepatic Insufficiency
A reduction in rhGH clearance has been noted in patients with severe liver dysfunction. The clinical significance of this decrease is unknown.
| Cmax (µg/L) | Tmax (hr) | t½ (hr) | AUC0-∞ (µg ∙ hr/L) | CL/Fsc (mL/[hr ∙ kg]) | |
|---|---|---|---|---|---|
| Abbreviations: | |||||
| Cmax=maximum concentration | |||||
| t½=half‑life | |||||
| AUC0-∞=area under the curve | |||||
| CL/Fsc=systemic clearance | |||||
| Fsc=subcutaneous bioavailability (not determined) | |||||
| CV%=coefficient of variation in %; SC=subcutaneous | |||||
Single Dose Mean Growth Hormone Concentrations in Healthy Adult Males
Clinical Studies
Nutropin Depot Growth Hormone Deficiency (GHD) in Pubertal Patients
One open‑label, multicenter, randomized clinical trial of two dosages of Nutropin was performed in pubertal patients with GHD. Ninety‑seven patients (mean age 13.9 years, 83 male, 14 female) currently being treated with approximately 0.3 mg/kg/wk of GH were randomized to 0.3 mg/kg/wk or 0.7 mg/kg/wk Nutropin doses. All patients were already in puberty (Tanner stage ≥2) and had bone ages ≤14 years in males or ≤12 years in females. Mean baseline height standard deviation (SD) score was –1.3.
The mean last measured height in all 97 patients after a mean duration of 2.7±1.2 years, by analysis of covariance (ANCOVA) adjusting for baseline height, is shown below.
| Last Measured Height* (cm) | Height Difference Between Groups (cm) | |||
|---|---|---|---|---|
| Age (yr) | 0.3 mg/kg/wk | 0.7 mg/kg/wk | ||
| Mean±SD (range) |
Mean±SD | Mean±SD | Mean±SE | |
|
||||
| Male | 17.2±1.3 (13.6 to 19.4) |
170.9±7.9 (n=42) |
174.5±7.9 (n=41) |
3.6±1.7 |
| Female | 15.8±1.8 (11.9 to 19.3) |
154.7±6.3 (n=7) |
157.6±6.3 (n=7) |
2.9±3.4 |
The mean height SD score at last measured height (n=97) was –0.7±1.0 in the 0.3 mg/kg/wk group and –0.1± 1.2 in the 0.7 mg/kg/wk group. For patients completing 3.5 or more years (mean 4.1 years) of Nutropin treatment (15/49 patients in the 0.3 mg/kg/wk group and 16/48 patients in the 0.7 mg/kg/wk group), the mean last measured height was 166.1±8.0 cm in the 0.3 mg/kg/wk group and 171.8±7.1 cm in the 0.7 mg/kg/wk group, adjusting for baseline height and sex.
The mean change in bone age was approximately one year for each year in the study in both dose groups. Patients with baseline height SD scores above –1.0 were able to attain normal adult heights with the 0.3 mg/kg/wk dose of Nutropin (mean height SD score at near‑adult height=–0.1, n=15).
Thirty‑one patients had bone mineral density (BMD) determined by dual energy x‑ray absorptiometry (DEXA) scans at study conclusion. The two dose groups did not differ significantly in mean SD score for total body BMD (–0.9±1.9 in the 0.3 mg/kg/wk group vs. –0.8±1.2 in the 0.7 mg/kg/wk group, n=20) or lumbar spine BMD (–1.0±1.0 in the 0.3 mg/kg/wk group vs. –0.2±1.7 in the 0.7 mg/kg/wk group, n=21).
Over a mean duration of 2.7 years, patients in the 0.7 mg/kg/wk group were more likely to have IGF‑I values above the normal range than patients in the 0.3 mg/kg/wk group (27.7% vs. 9.0% of IGF‑I measurements for individual patients). The clinical significance of elevated IGF‑I values is unknown.
Effects of Nutropin Depot on Growth Failure Due to Chronic Renal Insufficiency (CRI)
Two multicenter, randomized, controlled clinical trials were conducted to determine whether treatment with Nutropin prior to renal transplantation in patients with chronic renal insufficiency could improve their growth rates and height deficits. One study was a double‑blind, placebo‑controlled trial and the other was an open‑label, randomized trial. The dose of Nutropin in both controlled studies was 0.05 mg/kg/day (0.35 mg/kg/week) administered daily by subcutaneous injection. Combining the data from those patients completing two years in the two controlled studies results in 62 patients treated with Nutropin and 28 patients in the control groups (either placebo‑treated or untreated). The mean first year growth rate was 10.8 cm/yr for Nutropin‑treated patients, compared with a mean growth rate of 6.5 cm/yr for placebo/untreated controls (p<0.00005). The mean second year growth rate was 7.8 cm/yr for the Nutropin‑treated group, compared with 5.5 cm/yr for controls (p<0.00005). There was a significant increase in mean height standard deviation (SD) score in the Nutropin group (−2.9 at baseline to −1.5 at Month 24, n=62) but no significant change in the controls (−2.8 at baseline to −2.9 at Month 24, n=28). The mean third year growth rate of 7.6 cm/yr in the Nutropin‑treated patients (n=27) suggests that Nutropin stimulates growth beyond two years. However, there are no control data for the third year because control patients crossed over to Nutropin treatment after two years of participation. The gains in height were accompanied by appropriate advancement of skeletal age. These data demonstrate that Nutropin therapy improves growth rate and corrects the acquired height deficit associated with chronic renal insufficiency.
Post-Transplant Growth
The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has reported data for growth post‑transplant in children who did not receive GH prior to transplantation as well as children who did receive Nutropin during the clinical trials prior to transplantation. The average change in height SD score during the initial two years post transplant was 0.15 for the 2391 patients who did not receive GH pre-transplant and 0.28 for the 57 patients who did (J Pediatr. 2000;136:376-382). For patients who were followed for 5 years post-transplant, the corresponding changes in height SD score were also similar between groups.
Turner Syndrome
One long‑term, randomized, open‑label, multicenter, concurrently controlled study, two long‑term, open‑label, multicenter, historically controlled studies, and one long‑term, randomized, dose‑response study were conducted to evaluate the efficacy of GH for the treatment of girls with short stature due to Turner syndrome.
In the randomized study GDCT, comparing GH‑treated patients to a concurrent control group who received no GH, the GH‑treated patients who received a dose of 0.3 mg/kg/week given 6 times per week from a mean age of 11.7 years for a mean duration of 4.7 years attained a mean near final height of 146.0 cm (n=27) as compared to the control group who attained a near final height of 142.1 cm (n=19). By analysis of covariance, the effect of GH therapy was a mean height increase of 5.4 cm (p=0.001).
In two of the studies (85‑023 and 85‑044), the effect of long‑term GH treatment (0.375 mg/kg/week given either 3 times per week or daily) on adult height was determined by comparing adult heights in the treated patients with those of age‑matched historical controls with Turner syndrome who never received any growth‑promoting therapy. In Study 85‑023, estrogen treatment was delayed until patients were at least age 14. GH therapy resulted in a mean adult height gain of 7.4 cm (mean duration of GH therapy of 7.6 years) vs. matched historical controls by analysis of covariance.
In Study 85‑044, patients treated with early GH therapy were randomized to receive estrogen‑replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg daily) at either age 12 or 15 years. Compared with matched historical controls, early GH therapy (mean duration of GH therapy 5.6 years) combined with estrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm (n=26), whereas girls who initiated estrogen at age 15 years (mean duration of GH therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29). Patients who initiated GH therapy after age 11 (mean age 12.7 years; mean duration of GH therapy 3.8 years) had a mean adult height gain of 5.0 cm (n=51).
Thus, in both studies, 85‑023 and 85‑044, the greatest improvement in adult height was observed in patients who received early GH treatment and estrogen after age 14 years.
In a randomized, blinded, dose‑response study, GDCI, patients were treated from a mean age of 11.1 years for a mean duration of 5.3 years with a weekly dose of either 0.27 mg/kg or 0.36 mg/kg administered 3 or 6 times weekly. The mean near final height of patients receiving growth hormone was 148.7 cm (n=31). This represents a mean gain in adult height of approximately 5 cm compared with previous observations of untreated Turner syndrome girls.
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