Mecasermin rinfabate

Identification

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Name
Mecasermin rinfabate
Accession Number
DB14751
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Hormones
Description

Mecasermin rinfabate is approved for severe primary insulin-like growth factor (IGF) deficiency or in patients with GH gene deletion who have developed antibodies to growth hormone (GH)1. Mecasermin rinfabate is similar to Mecasermin in that both drugs contain recombinant DNA origin insulin-like growth factor 1 (IGF-1). Mecasermin rinfabate however, is already bound to recombinant DNA origin insulin-like growth factor binding protein 3 (IGFBP-3)3. The binding of IGF-1 to IGFBP-3 is said to extend the half life and reduce the clearance of IGF-1 in patients with growth hormone resistant syndromes and low levels of IGFBP-3 though this may represent <500 patients worldwide5.

Mecasermin rinfabate manufactured by Insmed Incorporated under the brand name Iplex was approved by the FDA in 20058. In 2007 Insmed withdrew their application for a marketing authorization with The European Medicines Agency10.

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • Mecasermin rinfabate
  • Mecasermin rinfabate recombinant
  • rhIGF-I/rhIGFBP-3
Categories
UNII
NZ8M50KKRG
CAS number
478166-15-3

Pharmacology

Indication

Mecasermin rinfabate was approved for treatment of severe primary insulin-like growth factor (IGF) deficiency or in patients with GH gene deletion who have developed antibodies to growth hormone (GH)1. Severe primary IGF-1 deficiency is defined by:Label

A) height standard deviation (SD) score less than or equal to 3 SD below normal

B) basal IGF-1 SD score less than or equal to 3 SD below normal

C) normal or above normal levels of growth hormone

In 2007, Insmed (Mecasermin rinfabate's manufacturer) made an agreement with Tercica (Mecasermin's manufacturer) that Mecasermin would no longer be available for this indication but could be developed for non short stature conditions such as severe insulin resistance, myotonic muscular dystrophy, and HIV associated adipose redistribution syndrome6.

Associated Conditions
Pharmacodynamics

Mecasermin rinfabate promotes vertical growth in pediatric patients in a similar fashion to MecaserminLabel.

Mecasermin is a biosynthetic (recombinant DNA origin) form of human insulin-like growth factor 1 (IGF-1) designed to replace natural IGF-1 in pediatric patients who are deficient, promoting normalized statural growth2. Growth hormones (GH) bind to growth hormone receptors (GHR) in the liver and other tissues, which stimulates the synthesis of IGF-1. In target tissues, IGF-1 activates the IGF-1 receptor, resulting in intracellular signals that stimulate growth 4. Although many actions of the GH are mediated through IGF-1, the precise roles of GH and IGF-1 have not been fully elucidated. Patients with severe primary IGF-1 deficiency (Primary IGFD) fail to produce adequate levels of IGF-1, due to disruption of the GH pathway used to promote IGF-1 release (possible GH pathway disruptions include mutations in the GHR, post-GHR signaling pathway, and IGF-1 gene defects5.

The structure of IGFBP-3 remains unsolved7.

Mechanism of action

Mecasermin rinfabate supplies recombinant-DNA-origin IGF-1 (rhIGF-1) bound to recombinant-DNA-origin IGFBP-3. 80% of IGF-1 is naturally bound to IGFBP-3 so the binding of rhIGF-1 to rhIGFBP-3 increases the half life of rhIGF-1 compared to Mecasermin. rhIGF-1 binds to the Type I IGF-1 receptor. This receptor exerts intra-cellular signaling activity in a number of processes involved in statural growth, including mitogenesis in multiple tissue types, chondrocyte growth and division along cartilage growth plates, and increases in organ growth2.

TargetActionsOrganism
AInsulin-like growth factor 1 receptor
agonist
Humans
UInsulin receptorNot AvailableHumans
UCation-independent mannose-6-phosphate receptorNot AvailableHumans
Absorption

There is little published data on the pharmacokinetics of Mecasermin rinfabate3. Mecasermin rinfabate is injected subcutaneously and distributes rapidly throughout the body, especially in well vascularized tissue9.

Volume of distribution

Approximately 1000mL/kg9.

Protein binding

Mecasermin rinfabate is formulated as two proteins (IGF-1 and IGFBP-3) already bound together in the same way they are naturally found in the human bodyLabel. This increases the serum half life of Mecasermin1.

Metabolism

There is little published data on the pharmacokinetics of Mecasermin rinfabate3. Mecasermin rinfabate is expected to degrade into small peptides and amino acids9. It is suspected that IGFBP-3 in Mecasermin rinfabate is broken down by serine proteases or metalloproteases3.

Route of elimination

An excretion study in monkeys showed elimination in the urine 72 hours after administration9.

Half life

Half life ranges from 10 to 16 hours with a mean of 13 hours9. Mecasermin rinfabate is said to have a longer half life than Mecasermin5.

Clearance

Clearance ranges from 50 to 56mL/hr/kg with a mean of 53mL/hr/kg9. Mecasermin rinfabate is said to have lower clearance than Mecasermin5

Toxicity

Studies on carcinogenicity, genotoxicity, animal fertility, fetal development, excretion in breast milk, and use in patients over 65 years have not been performedLabel. Use in pregnant, breast feeding, or geriatric populations should be avoided as there is a lack of safety dataLabel. Animal reproductive toxicity studies have shown increased incidence of abortion, post implantation loss, fewer viable fetuses, and an increase in fetal skeletal abnormalities9. Insulin-like growth factor 1 (IGF-1) without insulin-like growth factor binding protein 3 (IGFBP-3) has been shown to not be mutagenic according to the Ames test and have no affect on fertility in rats given 7 times the maximum human recommended dose based on body surface areaLabel. No studies have been performed in patients with impaired renal or hepatic function however these impairments are not expected to significantly affect the pharmacokinetics of Mecasermin rinfabate9.

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

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Kemp SF: Mecasermin rinfabate. Drugs Today (Barc). 2007 Mar;43(3):149-55. doi: 10.1358/dot.2007.43.3.1079876. [PubMed:17380212]
  2. Kemp SF: Insulin-like growth factor-I deficiency in children with growth hormone insensitivity: current and future treatment options. BioDrugs. 2009;23(3):155-63. doi: 10.2165/00063030-200923030-00002. [PubMed:19627167]
  3. Williams RM, McDonald A, O'Savage M, Dunger DB: Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX. Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):311-24. doi: 10.1517/17425255.4.3.311 . [PubMed:18363546]
  4. Rosenbloom AL: Mecasermin (recombinant human insulin-like growth factor I). Adv Ther. 2009 Jan;26(1):40-54. doi: 10.1007/s12325-008-0136-5. Epub 2009 Jan 28. [PubMed:19198769]
  5. Kemp SF, Fowlkes JL, Thrailkill KM: Efficacy and safety of mecasermin rinfabate. Expert Opin Biol Ther. 2006 May;6(5):533-8. doi: 10.1517/14712598.6.5.533 . [PubMed:16610982]
  6. Collett-Solberg PF, Misra M: The role of recombinant human insulin-like growth factor-I in treating children with short stature. J Clin Endocrinol Metab. 2008 Jan;93(1):10-8. doi: 10.1210/jc.2007-1534. Epub 2007 Dec 28. [PubMed:18165284]
  7. Forbes BE, McCarthy P, Norton RS: Insulin-like growth factor binding proteins: a structural perspective. Front Endocrinol (Lausanne). 2012 Mar 2;3:38. doi: 10.3389/fendo.2012.00038. eCollection 2012. [PubMed:22654863]
  8. FDA Drug Approval Package for Mecaserim Rinfabate [Link]
  9. European Medicines Agency Withdrawal Assessment Report For Mecasermin Rinfabate [File]
  10. Withdrawal Of Application For Mecasermin Rinfabate Marketing Authorization With European Medicines Agency [File]
External Links
Wikipedia
Mecasermin_rinfabate
ATC Codes
H01AC05 — Mecasermin rinfabate
FDA label
Download (477 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySolubleWilliams RM, McDonald A, O'Savage M, Dunger DB: Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX. Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):311-24. doi: 10.1517/17425255.4.3.311 . [PubMed:18363546]

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 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
References
  1. Rosenbloom AL: Mecasermin (recombinant human insulin-like growth factor I). Adv Ther. 2009 Jan;26(1):40-54. doi: 10.1007/s12325-008-0136-5. Epub 2009 Jan 28. [PubMed:19198769]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Curator comments
Mecasermin Rinfabate is likely to interact less with the Insulin Receptor than [DB01277] due to it being bound to IGFBP-3
General Function
Receptor signaling protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (...
Gene Name
INSR
Uniprot ID
P06213
Uniprot Name
Insulin receptor
Molecular Weight
156331.465 Da
References
  1. Rosenbloom AL: Mecasermin (recombinant human insulin-like growth factor I). Adv Ther. 2009 Jan;26(1):40-54. doi: 10.1007/s12325-008-0136-5. Epub 2009 Jan 28. [PubMed:19198769]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Transporter activity
Specific Function
Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate r...
Gene Name
IGF2R
Uniprot ID
P11717
Uniprot Name
Cation-independent mannose-6-phosphate receptor
Molecular Weight
274372.42 Da
References
  1. Rosenbloom AL: Mecasermin (recombinant human insulin-like growth factor I). Adv Ther. 2009 Jan;26(1):40-54. doi: 10.1007/s12325-008-0136-5. Epub 2009 Jan 28. [PubMed:19198769]

Drug created on March 04, 2019 16:14 / Updated on May 01, 2019 12:03