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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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Related in: MedlinePlus

Individual estimates of clearance (CL) vs. weight for adult and paediatric patients with haemophilia, based on PopPK analysis of data from Villar et al.[15]. Estimated linear relationship between CL and weight based on FVIIa clot activity assay (full line, open circles) and FVII:C activity assay (dashed line, filled circles). Based on FVIIa, (○—); Based on FVII:C, (• - - - -)
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fig02: Individual estimates of clearance (CL) vs. weight for adult and paediatric patients with haemophilia, based on PopPK analysis of data from Villar et al.[15]. Estimated linear relationship between CL and weight based on FVIIa clot activity assay (full line, open circles) and FVII:C activity assay (dashed line, filled circles). Based on FVIIa, (○—); Based on FVII:C, (• - - - -)

Mentions: Direct comparison of the results for adults and children (aged 18–55 and 2–12 years, respectively) by Villar et al.[15] indicated that plasma clearance was significantly (P < 0.05; NCA) higher in paediatric patients than in adults, using both the FVII:C and FVIIa clot activity assays. In contrast, there was only a nonsignificant trend towards an increased volume of distribution in children compared with adults and no difference in terminal half-life between the two groups (both P > 0.05). Subsequent analysis of these results by PopPK revealed no statistically significant (P > 0.01) differences in volumes of distribution between adults and children for either assay, while plasma clearance rates per kg body weight were higher in children (Kristensen, Klitgaard, data on file 2004). This difference reflects a higher metabolic activity in children than in adults per kg body weight and is possibly related to age-related differences in body composition, including differences in liver volume per kg body weight, as previously described in the literature [24, 25]. Mean population pharmacokinetic profiles for children and adults are shown in Figure 1, and the relationship between clearance and weight is illustrated in Figure 2.


Overview of the human pharmacokinetics of recombinant activated factor VII.

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

Individual estimates of clearance (CL) vs. weight for adult and paediatric patients with haemophilia, based on PopPK analysis of data from Villar et al.[15]. Estimated linear relationship between CL and weight based on FVIIa clot activity assay (full line, open circles) and FVII:C activity assay (dashed line, filled circles). Based on FVIIa, (○—); Based on FVII:C, (• - - - -)
© Copyright Policy
Related In: Results  -  Collection

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

fig02: Individual estimates of clearance (CL) vs. weight for adult and paediatric patients with haemophilia, based on PopPK analysis of data from Villar et al.[15]. Estimated linear relationship between CL and weight based on FVIIa clot activity assay (full line, open circles) and FVII:C activity assay (dashed line, filled circles). Based on FVIIa, (○—); Based on FVII:C, (• - - - -)
Mentions: Direct comparison of the results for adults and children (aged 18–55 and 2–12 years, respectively) by Villar et al.[15] indicated that plasma clearance was significantly (P < 0.05; NCA) higher in paediatric patients than in adults, using both the FVII:C and FVIIa clot activity assays. In contrast, there was only a nonsignificant trend towards an increased volume of distribution in children compared with adults and no difference in terminal half-life between the two groups (both P > 0.05). Subsequent analysis of these results by PopPK revealed no statistically significant (P > 0.01) differences in volumes of distribution between adults and children for either assay, while plasma clearance rates per kg body weight were higher in children (Kristensen, Klitgaard, data on file 2004). This difference reflects a higher metabolic activity in children than in adults per kg body weight and is possibly related to age-related differences in body composition, including differences in liver volume per kg body weight, as previously described in the literature [24, 25]. Mean population pharmacokinetic profiles for children and adults are shown in Figure 1, and the relationship between clearance and weight is illustrated in Figure 2.

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