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General Description:

Turoctocog alfa pegol, identified by CAS number 1309086-46-1, is a notable compound with significant therapeutic applications. Turoctocog alfa pegol is a pegylated version of . Novo Nordisk's brand name Esperoct (turoctocog alfa pegol, N8-GP) was approved by the US FDA on February 19, 2019. Fundamentally, the N8-GP moiety is identical to , a recombinant human clotting factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B-domain . Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human or animal-derived materials . During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this position is used in the purification process allowing isolation of the intact rFVIII . It was developed by Novo Nordisk and approved by the US FDA on October 16, 2013 . The essential difference between turoctocog alfa and N8-GP, however, is the specific attachment of a 40-kDa polyethylene glycol (PEG) group to a specific _O_-glycan in the truncated B-domain of the general turoctocog alfa rFVIII structure . This modification to the general turoctocog alfa rFVIII structure makes N8-GP an extended half-life factor VIII molecule for factor VIII replacement therapy in patients with factor VIII deficiency, or hemophilia A . As such, turoctocog alfa pegol is a valuable expansion to the drug therapies available for treating hemophilia A as it ultimately provides a less burdensome and more convenient dosing regimen for patients that is less frequent than that for turoctocog alfa.

Indications:

This drug is primarily indicated for: Turoctocog alfa pegol is indicated for use in adults and children with hemophilia A for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes. It is not indicated for the treatment of von Willebrand disease. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Turoctocog alfa pegol undergoes metabolic processing primarily in: Once activated by thrombin (clotting factor IIa), factor VIII dissociates from the stable non-covalent complex with von Willebrand Factor (vWF) that it generally circulates about in the blood with . Separated from the protection of its complexation with vWF, it is believed that factor VIII undergoes proteolysis into its component amino acids by phospholipid binding proteases like protein C and activated factor Xa before being cleared from the bloodstream . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Turoctocog alfa pegol are crucial for its therapeutic efficacy: Studies have determined that the pharmacokinetics of turoctocog alfa pegol (N8-GP) are dose linear . In particular, the area under the plasma activity curve from administration to infinity was a mean 14.74 +/- 5.35 (U h mL^-1), 38.85 +/- 11.41 (U h mL^-1), and 46.76 +/- 20.56 (U h mL^-1) at dosages of 25 U/kg, 50 U/kg, and 75 U/kg, respectively . Moreover, the C(30 min) factor VIII plasma activity 30 minutes after administration for the same three dosage categories was documented as being 0.65 +/- 0.12 U/mL, 1.24 +/- 0.28 U/mL, and 1.93 +/- 0.58 U/mL, respectively . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Turoctocog alfa pegol is an important consideration for its dosing schedule: The mean plasma half-life recorded for turoctocog alfa pegol (N8-GP) is 19.04 +/- 5.53 hours . Regardless, N8-GP is ultimately considered an extended half-life factor VIII molecule which offers a 1.6 fold half-life extension in adults and adolescents and a 1.9 fold half-life extension in children when compared the half-life of standard factor VIII medications . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Turoctocog alfa pegol exhibits a strong affinity for binding with plasma proteins: Data regarding the protein binding of turoctocog alfa pegol (N8-GP) is not readily available or accessible. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Turoctocog alfa pegol from the body primarily occurs through: Studies regarding the elimination and clearance of factor VIII propose that the clotting factor likely experiences clearance by way of tissue mechanisms such as receptor-mediated endocytosis followed by catabolism rather than hepatic metabolism and renal excretion . In particular, it is believed that receptor-mediated clearance of free factor VIII molecules is associated with structures like low-density lipoprotein (LDL) receptor-related protein (LRP1), LDL-receptors (LDLRs), heparan-sulfate proteoglycans (HSPG), megalin receptors, asialoglycoprotein receptors (ASGPRs), and various as of yet unidentified carbohydrate receptors . Some of these receptors may operate in association with each other, some may be able to internalize factor VIII by themselves, and some may be expressed on hepatocytes while still others may be expressed on macrophages . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Turoctocog alfa pegol is distributed throughout the body with a volume of distribution of: The mean volume of distribution recorded for turoctocog alfa pegol (N8-GP) is 45.27 +/- 17.78 mL/kg . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Turoctocog alfa pegol is a critical factor in determining its safe and effective dosage: The mean clearance recorded for turoctocog alfa pegol (N8-GP) is 1.79 +/- 0/92 (mL^-1 h^-1 kg^-1) . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Turoctocog alfa pegol exerts its therapeutic effects through: Based on results obtained from the Pathfinder clinical studies, turoctocog alfa pegol (N8-GP) was shown to provide effective routine prophylaxis in people with severe haemophilia A through a fixed dosing regimen of one injection every 4 days in adults and adolescents, or every 3-4 days (twice-weekly) in children . Furthermore, N8-GP provided effective prophylaxis and maintained a low median annualized bleeding rate (ABR) of 1.18 when administered at doses of 50 IU/kg every 4 days in adults and adolescents . Additionally, N8-GP was also found to be efficacious in the treatment and control of bleeding episodes and the perioperative management of bleeding . Across the clinical trials and age groups, N8-GP was shown to be well tolerated and no safety concerns were identified . The overall safety profile of N8-GP is similar to what has been reported for other long-action FVIII products . Moreover, in general, no FVIII inhibitor antibodies have been detected, and no thromboembolic events have occurred with the use of N8-GP . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Turoctocog alfa pegol functions by: The principal characteristic that defines hemophilia A is the limited presence or complete deficiency of human clotting factor VIII in the body . Subsequently, because factor VIII is a critical component that is essential for the extrinsic tissue factor pathway of the blood coagulation cascade process to proceed, individuals with hemophilia A ultimately experience increased bleeding - in comparison to individuals without a factor VIII deficiency - after injury or any kind of medical procedure . Such increased bleeding can be heavy and/or fatal and may occur due to minimal injury or even when there is no injury whatsoever - in which case the bleeding is spontaneous . Furthermore, excessive bleeds that bleed into muscles, organs, and joints are also associated with dangerous complications and regular pain . The turoctocog alfa pegol (N8-GP) drug is consequently recombinant factor VIII (rFVIII) in which specific site-directed glycoPEGylation has been performed in an effort to increase the half-life of the rFVIII moiety without altering its hemostatic activity . In particular, the general rFVIII component of N8-GP is turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B-domain . This glycoprotein has the same structure as human clotting factor VIII when activated, and also possesses post-translational modifications that are similar to those of the plasma-derived molecule . In blood, factor VIII predominantly circulates in a stable non-covalent complex with von Willebrand factor (vWF) . Concurrently, the tyrosine sulfation site present at the Tyr1680 (native full length) position, which is important for binding to vWF, has been found to be fully sulfated in the turoctocog alfa molecule . Subsequently, when infused into a hemophilia patient, this rFVIII binds to endogenous vWF in the patient’s circulation . The resultant factor VIII/vWF complex consists of two molecules (factor VIII and vWF) with different physiological functions . Factor VIII is activated by thrombin (factor IIa) . Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X . Activated factor X converts prothrombin into thrombin . Thrombin then converts fibrinogen into fibrin and a clot can be formed . Turoctocog alfa pegol consequently functions predominantly as factor VIII replacement therapy for patients with factor VIII deficient hemophilia A. Finally, the particular N8-GP molecule has a 40-kDa polyethylene glycol (PEG) attached to a specific _O_-glycan in the truncated B-domain of the general turoctocog alfa rFVIII structure . Upon activation by thrombin, this B-domain possessing the pegylation is cleaved away, leaving active rFVIIIa - which as discussed above, is highly similar to and elicits the same blood clotting activities as native factor VIII . Subsequently, the PEG group of N8-GP ultimately serves to extend the half-life of the overall drug molecule in the body. As an inert chemical, the PEG group prolongs N8-GP's half-life by acting like an obstructive 'cloud' around the rFVIII molecule to which it is attached . Since the PEG group is generally too large to be cleared by the kidneys and does not bind particularly well with the clearance receptors that typically eliminate endogenous factor VIII, N8-GP demonstrates a longer half-life than the general turoctocog alfa rFVIII structure . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Turoctocog alfa pegol 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:

Turoctocog alfa pegol is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Biological Factors, Blood Coagulation Factors, Blood Proteins, Factor VIII, Hemostatics, Proteins, Recombinant Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.