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Genotropin (Somatropin) - Description and Clinical Pharmacology

 
 



DESCRIPTION

GENOTROPIN Lyophilized Powder contains somatropin [rDNA origin], which is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,124 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin). GENOTROPIN is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone. GENOTROPIN is a sterile white lyophilized powder intended for subcutaneous injection.

GENOTROPIN 1.5 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 1.5 mg (approximately 4.5 IU), glycine 27.6 mg, sodium dihydrogen phosphate anhydrous 0.3 mg, and disodium phosphate anhydrous 0.3 mg; the rear chamber contains 1.13 mL water for injection.

GENOTROPIN 5.8 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 5.8 mg (approximately 17.4 IU), glycine 2.2 mg, mannitol 1.8 mg, sodium dihydrogen phosphate anhydrous 0.32 mg, and disodium phosphate anhydrous 0.31 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and mannitol 45 mg in 1.14 mL water for injection.

GENOTROPIN 13.8 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 13.8 mg (approximately 41.4 IU), glycine 2.3 mg, mannitol 14.0 mg, sodium dihydrogen phosphate anhydrous 0.47 mg, and disodium phosphate anhydrous 0.46 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and mannitol 32 mg in 1.13 mL water for injection.

GENOTROPIN MINIQUICK® is dispensed as a single-use syringe device containing a two-chamber cartridge. GENOTROPIN MINIQUICK is available as individual doses of 0.2 mg to 2.0 mg in 0.2-mg increments. The front chamber contains recombinant somatropin 0.22 to 2.2 mg (approximately 0.66 to 6.6 IU), glycine 0.23 mg, mannitol 1.14 mg, sodium dihydrogen phosphate 0.05 mg, and disodium phosphate anhydrous 0.027 mg; the rear chamber contains mannitol 12.6 mg in water for injection 0.275 mL.

GENOTROPIN is a highly purified preparation. The reconstituted recombinant somatropin solution has an osmolality of approximately 300 mOsm/kg, and a pH of approximately 6.7. The concentration of the reconstituted solution varies by strength and presentation (see HOW SUPPLIED).

CLINICAL PHARMACOLOGY

In vitro, preclinical, and clinical tests have demonstrated that GENOTROPIN Lyophilized Powder is therapeutically equivalent to human growth hormone of pituitary origin and achieves similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD) or Prader-Willi syndrome (PWS), or who were born small for gestational age (SGA), treatment with GENOTROPIN stimulates linear growth. In patients with GHD or PWS, treatment with GENOTROPIN also normalizes concentrations of IGF-I (Insulin-like Growth Factor-I/Somatomedin C). In adults with GHD, treatment with GENOTROPIN results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid metabolism, and normalization of IGF-I concentrations.

In addition, the following actions have been demonstrated for GENOTROPIN and/or somatropin.

  1. Tissue Growth
    1. Skeletal Growth:    GENOTROPIN stimulates skeletal growth in pediatric patients with GHD, PWS, or SGA. The measurable increase in body length after administration of GENOTROPIN results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are generally low in the serum of pediatric patients with GHD, PWS, or SGA, but tend to increase during treatment with GENOTROPIN. Elevations in mean serum alkaline phosphatase concentration are also seen.
    2. Cell Growth:    It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as compared with the normal pediatric population. Treatment with somatropin results in an increase in both the number and size of muscle cells.
  2. 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 GENOTROPIN.
  3. Carbohydrate Metabolism
    Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with GENOTROPIN. Large doses of growth hormone may impair glucose tolerance.
  4. Lipid Metabolism
    In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.
  5. Mineral Metabolism
    Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after therapy with GENOTROPIN. Serum calcium is not significantly altered by GENOTROPIN. Growth hormone could increase calciuria.
  6. Body Composition
    Adult GHD patients treated with GENOTROPIN at the recommended adult dose (see DOSAGE AND ADMINISTRATION) demonstrate a decrease in fat mass and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of GENOTROPIN is to modify body composition, an effect that is maintained with continued treatment.

PHARMACOKINETICS

ABSORPTION

Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN to adult GHD patients, approximately 80% of the dose was systemically available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been observed in healthy adult male subjects.

In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN was 35% greater than that for 1.3 mg/mL GENOTROPIN. The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL, respectively.

In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN. The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.

Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN at a concentration of 1.3 mg/mL, with a one- to four-week washout period between injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.

There are no data on the bioequivalence between the 12-mg/mL formulation and either the 1.3-mg/mL or the 5.3-mg/mL formulations.

DISTRIBUTION

The mean volume of distribution of GENOTROPIN following administration to GHD adults was estimated to be 1.3 (± 0.8) L/kg.

METABOLISM

The metabolic fate of GENOTROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN in normal adults is 0.4 hours, whereas subcutaneously administered GENOTROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.

EXCRETION

The mean clearance of subcutaneously administered GENOTROPIN in 16 GHD adult patients was 0.3 (± 0.11) L/hrs/kg.

SPECIAL POPULATIONS

Pediatric:    The pharmacokinetics of GENOTROPIN are similar in GHD pediatric and adult patients.

Gender:    No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of GENOTROPIN was similar in males and females.

Race:    No studies have been conducted with GENOTROPIN to assess pharmacokinetic differences among races.

Renal or hepatic insufficiency:    No studies have been conducted with GENOTROPIN in these patient populations.

Table 1 Mean SC Pharmacokinetic Parameters in Adult GHD Patients
Bioavailability
(%) (N=15)
Tmax
(hours) (N=16)
CL/F
(L/hr × kg) (N=16)
Vss/F
(L/kg) (N=16)
T1/2
(hours) (N=16)
Mean
(± SD)
80.5
*
5.9
(± 1.65)
0.3
(± 0.11)
1.3
(± 0.80)
3.0
(± 1.44)
95% CI 70.5 - 92.1 5.0 - 6.7 0.2 - 0.4 0.9 - 1.8 2.2 - 3.7
Tmax = time of maximum plasma concentration              T½  = terminal half-life
CL/F  = plasma clearance                                               SD = standard deviation
Vss/F = volume of distribution                                        CI  = confidence interval
* The absolute bioavailability was estimated under the assumption that the log-transformed data follow a normal distribution. The mean and standard deviation of the log-transformed data were mean = 0.22 (± 0.241).

CLINICAL STUDIES

ADULT PATIENTS WITH GROWTH HORMONE DEFICIENCY (GHD)

GENOTROPIN Lyophilized Powder 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 GENOTROPIN and 87 patients received placebo, followed by an open-label treatment period in which participating patients received GENOTROPIN for up to a total of 24 months. GENOTROPIN 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 GENOTROPIN 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.

PEDIATRIC PATIENTS WITH PRADER-WILLI SYNDROME (PWS)

The safety and efficacy of GENOTROPIN in the treatment of pediatric patients with Prader-Willi syndrome (PWS) were evaluated in two randomized, open-label, controlled clinical trials. Patients received either GENOTROPIN or no treatment for the first year of the studies, while all patients received GENOTROPIN during the second year. GENOTROPIN 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 GENOTROPIN at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received GENOTROPIN at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN at a dose of 0.36 mg/kg/week.

Patients who received GENOTROPIN showed significant increases in linear growth during the first year of study, compared with patients who received no treatment (see Table 2). Linear growth continued to increase in the second year, when both groups received treatment with GENOTROPIN.

Table 2 Efficacy of GENOTROPIN in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
Study 1 Study 2
GENOTROPIN
(0.24 mg/kg/week) n=15
Untreated
Control n=12
GENOTROPIN
(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
Height Standard Deviation Score (SDS) for age
   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
* p </= 0.001
**/* p </= 0.002 (when comparing SDS change at 12 months)

Changes in body composition were also observed in the patients receiving GENOTROPIN (see Table 3). 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 GENOTROPIN did not accelerate bone age, compared with patients who received no treatment.

Table 3
Effect of GENOTROPIN on Body Composition in Pediatric Patients with Prader-Willi Syndrome (Mean± SD)
GENOTROPIN 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
* p < 0.005**/* n=15 for the group receiving GENOTROPIN; n=12 for the Control group**/** n.s.

PEDIATRIC PATIENTS BORN SMALL FOR GESTATIONAL AGE (SGA) WHO FAIL TO MANIFEST CATCH-UP GROWTH BY AGE 2

The safety and efficacy of GENOTROPIN 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 GENOTROPIN (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 GENOTROPIN.

Patients who received any dose of GENOTROPIN showed significant increases in growth during the first 24 months of study, compared with patients who received no treatment (see Table 4). 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 4 Efficacy of GENOTROPIN in Children Born Small for Gestational Age (Mean ± SD)
GENOTROPIN
(0.24 mg/kg/week) n=76
GENOTROPIN
(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 -0.2 ± 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
* p = 0.0001 vs Untreated Control group**/* p = 0.0001 vs group treated with GENOTROPIN 0.24 mg/kg/week

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