Dibotermin alfa API Manufacturers

General Description:

Dibotermin alfa, identified by CAS number 246539-15-1, is a notable compound with significant therapeutic applications. Dibotermin alfa is a recombinant human bone morphogenetic protein-2 (rhBMP-2) derived from a recombinant Chinese Hamster Ovary (CHO) cell line . 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 . 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 . 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 . 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 . 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 .

Indications:

This drug is primarily indicated for: - 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 . - 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 . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Absorption:

The absorption characteristics of Dibotermin alfa are crucial for its therapeutic efficacy: 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 . Peak levels of circulating dibotermin alfa (0.1% of the implanted dose) were observed within 6 hours following implantation . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Dibotermin alfa is an important consideration for its dosing schedule: When injected intravenously, the terminal half-life of dibotermin alfa was 16 minutes in rats and 6.7 minutes in cynomolgus monkeys . This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Dibotermin alfa from the body primarily occurs through: As recombinant human bone morphogenetic protein-2 (BMP-2), dibotermin alfa is expected to undergo nonspecific protein degradation pathway shared by endogenous BMP-2. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Clearance:

The clearance rate of Dibotermin alfa is a critical factor in determining its safe and effective dosage: 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 . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Dibotermin alfa exerts its therapeutic effects through: Dibotermin alfa promotes bone and cartilage formation through anabolic effects in human osteoblastic cells . 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Dibotermin alfa functions by: 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 . 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) . 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 . 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 . 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 . At concentrations of 500 ng/mL, rhBMP-2 also enhanced the mRNA expression level of PTH/PTH related-peptide receptor in human bone cells . 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Dibotermin alfa belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Dibotermin alfa is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Biological Factors, Bone Morphogenetic Proteins, Drugs Affecting Bone Structure and Mineralization, Drugs for Treatment of Bone Diseases, Intercellular Signaling Peptides and Proteins, Musculo-Skeletal System, Peptides, Proteins, TGF-beta Superfamily Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.