Explore a selection of our essential drug information below, or:
Identification
- Generic Name
- Dibotermin alfa
- DrugBank Accession Number
- DB11639
- Background
Dibotermin alfa is a recombinant human bone morphogenetic protein-2 (rhBMP-2) derived from a recombinant Chinese Hamster Ovary (CHO) cell line Label. It is implanted in patients undergoing bone surgeries or those with fractures. BMPs are subfamily of the transforming growth factor-β (TGF-β) superfamily that have different actions on the bone matrix 2. BMP-2 is a potent osteoinductive protein that plays a critical role in the differentiation of osteoprogenitor cells into osteoblasts, thus promoting bone and cartilage formation 3. Through enhancing osteogenesis at the site of implantation, dibotermin alfa accelerates the healing of open tibial shaft fractures and reduces the need for secondary intervention 1. In a prospective clinical study of patients with an open tibial fracture, administration of dibotermin alfa resulted in faster fracture- or wound-healing, significantly fewer secondary invasive interventions, and reduced infection rate post-operation 1. Dibotermin alfa was approved by the EMA in 2002 as Inductos for implantation matrix. In 2004, it was approved by the FDA and is marketed as Infuse. In Infuse, rhBMP is a disulfide-linked dimeric protein molecule with two major subunit species of 114 and 131 amino acids. Each subunit is glycosylated with high-mannose-type glycans Label.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Other protein based therapies - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- BMP 2
- BMP-2
- Bone morphogenetic protein 2
- Bone morphogenetic protein 2 (human recombinant rhBMP-2)
- Dibotermin alfa
- Dibotermina alfa
- rhBMP-2
Pharmacology
- Indication
- indicated for the treatment of acute tibia fractures in adults, as an adjunct to standard care using open fracture reduction and intramedullary unreamed nail fixation Label.
- indicated for single-level lumbar interbody spine fusion as a substitute for autogenous bone graft in adults with degenerative disc disease who have had at least 6 months of non-operative treatment for this condition 5.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Tibial fractures •••••••••••• ••••• ••••••• - Associated Therapies
- Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Dibotermin alfa promotes bone and cartilage formation through anabolic effects in human osteoblastic cells 3. Radiographic, biomechanical and histologic evaluation of the induced bone at the site of implantation supports that induced bone from dibotermin alfa therapy is capable of biological and biochemical function as native bone and repair abilities 5.
- Mechanism of action
In the same pathway shared by endogenous BMPs, recombinant human BMP-2 (rhBMP-2) binds and initiates intracellular signal cascade through an oligomeric transmembrane receptor complex formed by type I and II serine/threonine kinase receptor proteins 4. These BMP receptors are expressed on the surface of mesenchymal cells and upon binding of BMP-2 to the BMP receptor type II, type II receptor phosphorylates and activates type I receptor. Type I receptor may also undergo autophosphorylation. Activated BMP type I receptor then phosphorylates intracellular effector proteins, the receptor-regulated Smads (R-Smads) 2. Smad1, Smad 5 and Smad 8 associate with the Co-Smad, Smad4 and once activated via complex formation, they translocate to the nucleus where they associate with other transcription factors and bind promoters of target genes to control their expression 2. This ultimately results in bone formation at the site of implantation. Dibotermin alfa causes mesenchymal cells to differentiate into cartilage- and bone-forming cells. Implantation of dibotermin alfa in trabecular bone results in transient resorption of the bone surrounding the implant, followed by replacement of degraded matrix by newly differentiated cells 5.
In human bone cells isolated from adult mandibulae, recombinant human BMP-2 (rhBMP-2) was shown to stimulate the activity of early biomarkers of osteoblast differentiation, including alkaline phosphatase and parathyroid hormone (PTH)-dependent 3', 5'-cyclic adenosine monophosphate accumulation 3. At concentrations of 500 ng/mL, rhBMP-2 also enhanced the mRNA expression level of PTH/PTH related-peptide receptor in human bone cells 3. There was evidence that rhBMP-2 inhibits 1,25-dihydroxyvitamin D3-induced osteocalcin synthesis at both the mRNA and protein level. rhBMP-2 also significantly suppressed MMP-1 production and MMP-1 mRNA expression at concentrations exceeding 500 ng/mL 3.
Target Actions Organism ABone morphogenetic protein receptor type-2 ligandHumans ABone morphogenetic protein receptor type-1A ligandHumans - Absorption
Dibotermin alfa is active at the site of implantation with no detection in the serum. In rat studies with radiolabelled dibotermin alfa, the mean residence time at the site of implantation was 4-8 days 5. Peak levels of circulating dibotermin alfa (0.1% of the implanted dose) were observed within 6 hours following implantation 5.
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
As recombinant human bone morphogenetic protein-2 (BMP-2), dibotermin alfa is expected to undergo nonspecific protein degradation pathway shared by endogenous BMP-2.
- Half-life
When injected intravenously, the terminal half-life of dibotermin alfa was 16 minutes in rats and 6.7 minutes in cynomolgus monkeys 5.
- Clearance
At the site of implantation, dibotermin alfa is expected to be slowly released from the matrix and rapidly cleared when taken up into the systemic circulation 5.
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Supportive treatment is recommended in case of overdose. Use of Inductos in patients undergoing cervical spine surgery in amounts lower than or similar to those for lumbar interbody fusion has been associated with reports of localised oedema severe enough to result in airway compromise 5.
There is no evidence of significant hazards on humans based on non-clinical data of acute and repeated exposure toxicity and genotoxicity studies 5. In reproductive toxicity studies in rats, intravenous administration of dibotermin alfa was associated with increased fetal weight and increased fetal ossification. The clinical relevance of this effect is unknown 5. In human tumour cell lines in vitro, dibotermin alfa did not display any potential for promotion of tumour growth or metastasis 5. Studies investigating the carcinogenicity of dibotermin alfa have not been conducted.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Inductos 1.5 mg/ml Medtronic Bio Pharma B.V. 2020-12-20 Not applicable EU 
Inductos 1.5 mg/ml Medtronic Bio Pharma B.V. 2020-12-20 Not applicable EU
Categories
- ATC Codes
- M05BC01 — Dibotermin alfa
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- T472P45MG6
- CAS number
- 246539-15-1
References
- General References
- Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T: Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002 Dec;84-A(12):2123-34. [Article]
- Lissenberg-Thunnissen SN, de Gorter DJ, Sier CF, Schipper IB: Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop. 2011 Sep;35(9):1271-80. doi: 10.1007/s00264-011-1301-z. Epub 2011 Jun 23. [Article]
- Takiguchi T, Kobayashi M, Suzuki R, Yamaguchi A, Isatsu K, Nishihara T, Nagumo M, Hasegawa K: Recombinant human bone morphogenetic protein-2 stimulates osteoblast differentiation and suppresses matrix metalloproteinase-1 production in human bone cells isolated from mandibulae. J Periodontal Res. 1998 Nov;33(8):476-85. [Article]
- Ghodadra N, Singh K: Recombinant human bone morphogenetic protein-2 in the treatment of bone fractures. Biologics. 2008 Sep;2(3):345-54. [Article]
- EMA Label: InductOs Summary of Product Characteristics [Link]
- External Links
- UniProt
- P12643
- Wikipedia
- Bone_morphogenetic_protein_2
- FDA label
- Download (713 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Treatment Periodontitis 1 somestatus stop reason just information to hide Not Available Not Yet Recruiting Not Available Bone Loss 1 somestatus stop reason just information to hide Not Available Not Yet Recruiting Treatment Osteoporosis / Spine Fusion 1 somestatus stop reason just information to hide 4 Completed Treatment Tibial Fractures 1 somestatus stop reason just information to hide 4 Terminated Basic Science Lumbar Spine Degeneration 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Implant Intracavitary 1.5 mg/ml - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Ligand
- General Function
- On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Can also mediate signaling through the activation of the p38MAPK cascade (PubMed:12045205). Binds to BMP7, BMP2 and, less efficiently, BMP4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Mediates induction of adipogenesis by GDF6
- Specific Function
- activin receptor activity, type II
- Gene Name
- BMPR2
- Uniprot ID
- Q13873
- Uniprot Name
- Bone morphogenetic protein receptor type-2
- Molecular Weight
- 115200.475 Da
References
- Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T: Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002 Dec;84-A(12):2123-34. [Article]
- Ghodadra N, Singh K: Recombinant human bone morphogenetic protein-2 in the treatment of bone fractures. Biologics. 2008 Sep;2(3):345-54. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Ligand
- General Function
- On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP2, BMP4, GDF5 and GDF6. Positively regulates chondrocyte differentiation through GDF5 interaction. Mediates induction of adipogenesis by GDF6. May promote the expression of HAMP, potentially via its interaction with BMP2 (By similarity)
- Specific Function
- ATP binding
- Gene Name
- BMPR1A
- Uniprot ID
- P36894
- Uniprot Name
- Bone morphogenetic protein receptor type-1A
- Molecular Weight
- 60196.915 Da
References
- Nickel J, Dreyer MK, Kirsch T, Sebald W: The crystal structure of the BMP-2:BMPR-IA complex and the generation of BMP-2 antagonists. J Bone Joint Surg Am. 2001;83-A Suppl 1(Pt 1):S7-14. [Article]
- Kirsch T, Nickel J, Sebald W: Isolation of recombinant BMP receptor IA ectodomain and its 2:1 complex with BMP-2. FEBS Lett. 2000 Feb 25;468(2-3):215-9. [Article]
- Kirsch T, Nickel J, Sebald W: BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II. EMBO J. 2000 Jul 3;19(13):3314-24. doi: 10.1093/emboj/19.13.3314. [Article]
- Gilboa L, Nohe A, Geissendorfer T, Sebald W, Henis YI, Knaus P: Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell. 2000 Mar;11(3):1023-35. [Article]
Drug created at October 17, 2016 21:29 / Updated at February 21, 2021 18:53