Turoctocog alfa pegol

Uses

Turoctocog alfa pegol (N8-GP) is indicated for use in adults and children of all ages with hemophilia A (congenital factor VIII deficiency) for routine prophylaxis in reducing the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and the perioperative management of bleeding .

Turoctocog alfa pegol is also used to associated treatment for these conditions: Bleeding

How Turoctocog alfa pegol works

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 .

Toxicity

At the moment, due to third-party IP agreements, Novo Nordisk will not be able to launch the retail ESPEROCT® (turoctocog alfa pegol) product before 2020 in the USA . Subsequently, despite a relative lack of toxicity data - from clinical studies, post-marketing surveillance, or otherwise - general experience with the medication has suggested that it is well tolerated across all age groups and indications, and no safety concerns were identified after more than 5 years of clinical exposure .

Volume of Distribution

The mean volume of distribution recorded for turoctocog alfa pegol (N8-GP) is 45.27 +/- 17.78 mL/kg .

Elimination Route

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 .

Half Life

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 .

Clearance

The mean clearance recorded for turoctocog alfa pegol (N8-GP) is 1.79 +/- 0/92 (mL^-1 h^-1 kg^-1) .

Elimination Route

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 .

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