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Overview of the human pharmacokinetics of recombinant activated factor VII.

Klitgaard T, Nielsen TG - Br J Clin Pharmacol (2007)

Bottom Line: Plasma clearance was a more robust parameter than half-life for comparing rFVIIa pharmacokinetics between groups.Comparison of plasma clearance rates in different patient populations suggested that subjects fall into two distinct groups.These differences may have clinical implications in terms of how to adapt the rFVIIa dosing regimen, depending on the expected bleeding rate/blood loss and underlying disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomodelling, Novo Nordisk A/S, Bagsvaerd, Denmark. tkt@novonordisk.com

ABSTRACT

Aims: To review the pharmacokinetics of rFVIIa in various patient populations, and to discuss the differences observed between groups.

Methods: Based on a registry of Novo Nordisk studies, 14 studies evaluating rFVIIa pharmacokinetics following single and multiple bolus administration in healthy volunteers, adult and paediatric patients with congenital haemophilia and inhibitors, patients undergoing liver surgery and in patients with cirrhosis, inherited FVII deficiency, upper gastrointestinal bleeding or severe trauma were identified. Data on rFVIIa PK, analyzed with noncompartmental and population pharmacokinetic methods, were extracted.

Results: Plasma clearance was a more robust parameter than half-life for comparing rFVIIa pharmacokinetics between groups. In healthy volunteers and patients with no or low-level bleeding (e.g. adults with haemophilia, nonbleeding patients with cirrhosis), plasma clearance was relatively low (30-40 ml kg(-1) h(-1)). In children with haemophilia and adults with high-level bleeding (e.g. cirrhotic patients undergoing orthotopic liver transplantation or resection) and patients with congenital FVII deficiency, plasma clearance was relatively higher (60-90 ml kg(-1) h(-1)).

Conclusions: Comparison of plasma clearance rates in different patient populations suggested that subjects fall into two distinct groups. These differences may have clinical implications in terms of how to adapt the rFVIIa dosing regimen, depending on the expected bleeding rate/blood loss and underlying disease.

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Population pharmacokinetic profiles of rFVIIa after administration of three doses (200, 100 and 100 μg/kg) at 0, 1 and 3 h, simulated for various postdose RBC transfusion requirements. Based on PopPK analysis of data in trauma patients [23]. Figure adapted from [23] by kind permission of BioMed Central. RBC = 8.7 units (mean), (); RBC = 20 units, (······); RBC = 30 units, (––); RBC = 40 units, (- - - -)
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fig04: Population pharmacokinetic profiles of rFVIIa after administration of three doses (200, 100 and 100 μg/kg) at 0, 1 and 3 h, simulated for various postdose RBC transfusion requirements. Based on PopPK analysis of data in trauma patients [23]. Figure adapted from [23] by kind permission of BioMed Central. RBC = 8.7 units (mean), (); RBC = 20 units, (······); RBC = 30 units, (––); RBC = 40 units, (- - - -)

Mentions: Using this model, a patient receiving no RBC transfusions or 40 units of RBC after the first dose of rFVIIa would have a predicted clearance of approximately 36 ml kg−1 h−1 and 62 ml kg−1 h−1, respectively. The effect on the simulated population pharmacokinetic profiles is illustrated in Figure 4. The high variation in clearance, and the implications for the pharmacokinetic profile, suggests that a repeat dose regimen may be required for maintaining a minimum effective FVII coagulant activity level throughout this heterogeneous patient population.


Overview of the human pharmacokinetics of recombinant activated factor VII.

Klitgaard T, Nielsen TG - Br J Clin Pharmacol (2007)

Population pharmacokinetic profiles of rFVIIa after administration of three doses (200, 100 and 100 μg/kg) at 0, 1 and 3 h, simulated for various postdose RBC transfusion requirements. Based on PopPK analysis of data in trauma patients [23]. Figure adapted from [23] by kind permission of BioMed Central. RBC = 8.7 units (mean), (); RBC = 20 units, (······); RBC = 30 units, (––); RBC = 40 units, (- - - -)
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2291262&req=5

fig04: Population pharmacokinetic profiles of rFVIIa after administration of three doses (200, 100 and 100 μg/kg) at 0, 1 and 3 h, simulated for various postdose RBC transfusion requirements. Based on PopPK analysis of data in trauma patients [23]. Figure adapted from [23] by kind permission of BioMed Central. RBC = 8.7 units (mean), (); RBC = 20 units, (······); RBC = 30 units, (––); RBC = 40 units, (- - - -)
Mentions: Using this model, a patient receiving no RBC transfusions or 40 units of RBC after the first dose of rFVIIa would have a predicted clearance of approximately 36 ml kg−1 h−1 and 62 ml kg−1 h−1, respectively. The effect on the simulated population pharmacokinetic profiles is illustrated in Figure 4. The high variation in clearance, and the implications for the pharmacokinetic profile, suggests that a repeat dose regimen may be required for maintaining a minimum effective FVII coagulant activity level throughout this heterogeneous patient population.

Bottom Line: Plasma clearance was a more robust parameter than half-life for comparing rFVIIa pharmacokinetics between groups.Comparison of plasma clearance rates in different patient populations suggested that subjects fall into two distinct groups.These differences may have clinical implications in terms of how to adapt the rFVIIa dosing regimen, depending on the expected bleeding rate/blood loss and underlying disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomodelling, Novo Nordisk A/S, Bagsvaerd, Denmark. tkt@novonordisk.com

ABSTRACT

Aims: To review the pharmacokinetics of rFVIIa in various patient populations, and to discuss the differences observed between groups.

Methods: Based on a registry of Novo Nordisk studies, 14 studies evaluating rFVIIa pharmacokinetics following single and multiple bolus administration in healthy volunteers, adult and paediatric patients with congenital haemophilia and inhibitors, patients undergoing liver surgery and in patients with cirrhosis, inherited FVII deficiency, upper gastrointestinal bleeding or severe trauma were identified. Data on rFVIIa PK, analyzed with noncompartmental and population pharmacokinetic methods, were extracted.

Results: Plasma clearance was a more robust parameter than half-life for comparing rFVIIa pharmacokinetics between groups. In healthy volunteers and patients with no or low-level bleeding (e.g. adults with haemophilia, nonbleeding patients with cirrhosis), plasma clearance was relatively low (30-40 ml kg(-1) h(-1)). In children with haemophilia and adults with high-level bleeding (e.g. cirrhotic patients undergoing orthotopic liver transplantation or resection) and patients with congenital FVII deficiency, plasma clearance was relatively higher (60-90 ml kg(-1) h(-1)).

Conclusions: Comparison of plasma clearance rates in different patient populations suggested that subjects fall into two distinct groups. These differences may have clinical implications in terms of how to adapt the rFVIIa dosing regimen, depending on the expected bleeding rate/blood loss and underlying disease.

Show MeSH
Related in: MedlinePlus