Somatrem

Identification

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Name
Somatrem
Accession Number
DB09098
Type
Biotech
Groups
Approved, Investigational, Withdrawn
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

In 1985 somatrem (methionyl-growth hormone) became the first recombinant growth hormone product to be marketed commercially (Protropin by Genentech) [3]. The agent has the same amino acid sequence as human growth hormone except for an extra methionine at the end of the sequence chain to facilitate its manufacturing process [3].

Although the first commercially marketed recombinant growth hormone product Protropin was discontinued in 2004 owing to a relative explosion in brand and generic based releases of competing companies' own recombinant growth hormone products and the ensuing competition in product price over the years, many companies now produce and sell various approved formulations of methionyl-growth hormone, including Genetech's own current Nutropin product [3].

Despite the ability of almost all contemporary recombinant growth hormones to cause definite and demonstrable increases in growth rate in patients who are administered the drug, the use of these agents continues to be mired in persistent bioethical debate [1]. Such discussion revolves around whether patients' natural disposition of short stature should be considered a medical condition justifying medical treatment with such hormone therapy - especially when these hormone agents have been proven effective at increasing the height of children with or without growth hormone deficiency [1].

Protein structure
Db09098
Protein chemical formula
C995H1537N263O301S8
Protein average weight
22255.9518 Da
Sequences
Not Available
Synonyms
  • Somatrem (genetical recombination)
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Protropin - Kit Im Sc 10mg/vialSomatrem (10 mg) + Water (10 ml)Liquid; Powder, for solutionIntramuscular; SubcutaneousHoffmann La Roche1998-05-132005-02-16Canada
Protropin - Kit Im Sc 5mg/vialSomatrem (5 mg) + Water (10 ml)Liquid; Powder, for solutionIntramuscular; SubcutaneousHoffmann La Roche1998-06-292003-07-30Canada
Protropin Inj Pws 10mg/vialSomatrem (10 mg) + Water (20 ml)Liquid; Powder, for solutionIntramuscularGenentech, Inc.1992-12-311998-08-12Canada
Protropin Pws 5mg/vialSomatrem (5 mg) + Water (10 ml)Powder, for solutionIntramuscularGenentech, Inc.1986-12-311998-07-14Canada
Categories
UNII
CU8D464EDW
CAS number
82030-87-3

Pharmacology

Indication

Somatrem is a recombinant human growth hormone indicated for: (a) treatment of paediatric patients with growth failure due to growth hormone deficiency (GHD), (b) treatment of paediatric patients with growth failure due to idiopathic short stature (ISS), (c) treatment of paediatric patients with growth failure due to Turner syndrome (TS), (d) treatment of paediatric patients with growth failure due to chronic kidney disease (CKD) up to the time of renal transplantation, (e) treatment of adults with childhood-onset GHD, or (f) treatment of adults with adult-onset GHD [Label].

Pharmacodynamics

In vitro and in vivo preclinical and clinical testing have demonstrated that somatrem is therapeutically equivalent to pituitary derived human growth hormone (hGH) [2, Label]. Paediatric patients who lack adequate endogenous growth hormone secretion, patients with chronic kidney disease, and patients with Turner syndrome that were treated with somatrem resulted in an increase in growth rate and an increase in insulin-like growth factor (IGF-1) levels similar to that seen with patients who possess endogenous pituitary derived hGH [2, Label]. With normalized levels of growth hormone and related mediator agents like IGF-1, patients demonstrate normalized skeletal, cell, organ, and overall tissue growth [2, Label].

Mechanism of action

Somatrem - as well as endogenous growth hormone - binds to dimeric growth hormone (GH) receptors located within the cell membranes of target tissue cells resulting in intracellular signal transduction and a host of pharmacodynamic effects [2, Label]. Some of these pharmacodynamic effects are primarily mediated by insulin like growth factor (IGF-1) produced in the liver and also locally (ie. skeletal growth, protein synthesis), while others are primarily a consequence of the direct effects of somatropin (ie. lipolysis) [2, Label].

Skeletal growth is accomplished at the epiphyseal plates at the ends of growing bone [Label]. Growth and metabolism of epiphyseal plate cells are directly stimulated by GH and its mediator IGF-I [Label]. Serum levels of IGF-I are low in children and adolescents who are growth hormone deficient, but increase during somatrem treatment [Label]. New bone is consequently formed at the epiphyses for paediatric patients in response to GH and IGF-I from somatrem treatment [Label]. This results in linear growth until these growth plates fuse at the end of puberty [Label].

Somatrem treatment also causes an increase in both the number and the size of skeletal muscle cells [Label]. Additionally, such therapy also influences the size of internal organs, including kidneys, and increases red cell mass [Label].

Linear skeletal bone growth is facilitated in part by GH-stimulated protein synthesis [Label]. This is demonstrated by nitrogen retention as reflected by a decline in urinary nitrogen excretion and blood urea nitrogen (BUN) during somatrem therapy [Label]. GH also acts as a modulator of carbohydrate metabolism which may improve a fasting hypoglycaemia feeling that some patients with inadequate GH secretion sometimes experience [Label]. Additionally, somatrem administration may decrease insulin sensitivity, resulting in increased serum fasting and postprandial insulin levels - usually more commonly in overweight or obese individuals, adults or children [Label]. Moreover, mean fasting and postprandial glucose and hemoglobin A1C levels remained in the normal range [Label].

Furthermore, in growth hormone deficient patients, the use of somatrem resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels [Label]. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH, chronic kidney disease, or Turner syndrome during somatrem therapy due to metabolic activity associated with bone growth as well as increased tubular reabsorption of phosphate by the kidney [Label]. Serum calcium is not significantly altered in somatrem patients [Label]. Sodium retention and increases in serum alkaline phosphatase can occur to patients taking somatrem [Label]. As well, GH can stimulate the synthesis of chondroitin sulphate and collagen as well as the urinary excretion of hydroxyproline [Label].

TargetActionsOrganism
AGrowth hormone receptor
agonist
Humans
AInsulin-like growth factor 1 receptorNot AvailableHumans
Absorption

The absolute bioavailability of somatrem after subcutaneous administration in healthy adult males has been determined to be 81 +/- 20%. Additionally, as the subcutaneous terminal half-life is significantly longer than the intravenous terminal half-life, it appears as if the subcutaneous absorption of somatrem is slow and rate-limiting [2, Label].

Volume of distribution

Animal studies with somatrem showed that growth hormone localizes to highly perfused organs, particularly the liver and kidney [2, Label]. The volume of distribution at steady state for somatrem in health adult males is approximately 50 mL/kg body weight, approximating the serum volume [2, Label].

Protein binding
Not Available
Metabolism

Both the liver and kidney have been shown to be important metabolizing organs for growth hormone [2, Label]. Animal studies suggest that the kidney is the dominant organ of clearance. Growth hormone is filtered at the glomerulus and reabsorbed in the proximal tubules [2, Label]. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation [2, Label].

Route of elimination

Animal studies suggest that the kidney is the dominant organ of clearance [2, Label].

Half life

The mean terminal half-life after subcutaneous administration is 2.1 +/- 0.43 hours while the mean terminal half-life after intravenous administration is determined to be 19.5 +/- 3.1 minutes [2, Label].

Clearance

The clearance of somatrem after intravenous administration in healthy adults and children is reported to be in the range of 116-174 mL/hr/kg [2, Label].

Toxicity

Short-term overdosage with somatrem may initially result in hypoglycaemia and then subsequently to hyperglycemia [2, Label]. Moreover, this kind of short-term overdosage with somatrem is also likely to cause fluid retention [2, Label].

Long-term overdose with somatrem could leads to signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone [2, Label].

Some animal based oral LD50 values have been reported as: mouse = 300mg/kg, rabbit = 3200 mg/kg, rat = 980 mg/kg.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
Cortisone acetateThe serum concentration of the active metabolites of Cortisone acetate can be reduced when Cortisone acetate is used in combination with Somatrem resulting in a loss in efficacy.
MacimorelinThe therapeutic efficacy of Macimorelin can be decreased when used in combination with Somatrem.
Food Interactions
Not Available

References

General References
  1. Allen DB, Fost N: hGH for short stature: ethical issues raised by expanded access. J Pediatr. 2004 May;144(5):648-52. doi: 10.1016/j.jpeds.2004.02.028. [PubMed:15127004]
  2. Human Growth Hormone: Protropin [Link]
  3. Wikipedia: Growth Hormone Therapy [Link]
External Links
KEGG Drug
D05884
PubChem Substance
347910403
Wikipedia
Somatrem
ATC Codes
H01AC02 — Somatrem
FDA label
Download (420 KB)
MSDS
Download (78.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableGrowth Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Liquid; powder, for solutionIntramuscular; Subcutaneous
Liquid; powder, for solutionIntramuscular
Powder, for solutionIntramuscular
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Protein kinase binding
Specific Function
Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity).The soluble form (GHBP) acts as a rese...
Gene Name
GHR
Uniprot ID
P10912
Uniprot Name
Growth hormone receptor
Molecular Weight
71498.885 Da
Kind
Protein
Organism
Humans
Pharmacological action
Yes
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involv...
Gene Name
IGF1R
Uniprot ID
P08069
Uniprot Name
Insulin-like growth factor 1 receptor
Molecular Weight
154791.73 Da

Drug created on September 16, 2015 14:43 / Updated on November 02, 2018 06:58