title: Pharmacokinetic characterization of recombinant factor XIII (FXIII)-A2 across age groups in patients with FXIII A-subunit congenital deficiency.
abstract: Three trials investigated the pharmacokinetics (PK) of recombinant factor XIII (rFXIII) A-subunit. To compare the PK characteristics of rFXIII among trials and different age groups of patients. Dosing with rFXIII 35 IU kg(-1) every 4th week. Blood samples for PK assessments were collected regularly throughout the dosing interval from a total of 68 individual patients with FXIII congenital deficiency. The mean PK parameters were similar across the three age groups, and for the three trials, as well as constant over time based on results from patients participating in both mentor 1 and mentor 2 trials. The geometric mean half-life ranged from 11.6 to 15.0 days, and the trough FXIII activity levels ranged from 0.15 to 0.21 IU mL(-1) . The population PK model identified body weight as a statistically significant covariate influencing clearance (CL) and volume of distribution (Vd ), with a similar increase in both parameters with increased body weight. The half-life was not affected by body weight. Gender (females vs. males) and age category (paediatric vs. adult) did not affect CL. The PK profile of rFXIII, after dosing with 35 IU kg(-1) of rFXIII, was independent of age and comparable between trials and FXIII trough activity levels were constant. Despite rather large individual variation in the maximal FXIII activity levels, all individual mean trough activity levels were above 0.1 IU mL(-1) during the entire duration of the trials. The results support that monthly dosing with 35 IU kg(-1) of rFXIII to patients with FXIII A-subunit deficiency, regardless of age, is adequate for prophylaxis.
authors: Division of Haematology, University Hospital Zurich, Zurich, Switzerland.
authors: B
authors: B
authors: Brand-Staufer
authors: Division of Haematology/Oncology and Child Health Evaluative Sciences, Department of Paediatrics, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
authors: M
authors: M
authors: Carcao
authors: Nationwide Children's Hospital, Columbus, OH, USA.
authors: B A
authors: BA
authors: Kerlin
authors: Royal Manchester Children's Hospital, Manchester, UK.
authors: A
authors: A
authors: Will
authors: Birmingham Children's Hospital, Birmingham, UK.
authors: M
authors: M
authors: Williams
authors: Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark.
authors: C W
authors: CW
authors: Tornøe
authors: Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark.
authors: M
authors: M
authors: Sandberg Lundblad
authors: Children's Hospital of Orange County, Children's Hospital and Center for Inherited Blood Disorders, Orange, CA, USA.
authors: D
authors: D
authors: Nugent
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005176:Factor XIII / Q000737:chemistry / Q000235:genetics*; D005177:Factor XIII Deficiency / Q000188:drug therapy* / Q000235:genetics*; D026122:Factor XIIIa / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics*; D011994:Recombinant Proteins / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D021122:Protein Subunits; D011994:Recombinant Proteins; C521905:recombinant factor XIII-A2; D005176:Factor XIII; D026122:Factor XIIIa
keywords: factor XIII; pharmacokinetics; recombinant factor XIII
references: Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14: 1190-200.
references: Peyvandi F, Cattaneo M, Inbal A, De Moerloose P, Spreafico M. Rare bleeding disorders. Haemophilia 2008; 14(Suppl. 3): 202-10.
references: Lovejoy AE, Reynolds TC, Visich JE et al. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency. Blood 2006; 108: 57-62.
references: Inbal A, Oldenburg J, Carcao M, Rosholm A, Tehranchi R, Nugent D. Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency. Blood 2012; 119: 5111-7.
references: Kerlin B, Brand B, Inbal A et al. Pharmacokinetics of recombinant FXIII at steady-state in patients with congenital FXIII A-subunit deficiency. J Thromb Haemost 2014. doi: 10.1111/jth.12739.
references: Williams M, Will A, Stenmo C, Rosholm A, Tehranchi R. Pharmacokinetics of recombinant factor XIII in young children with congenital FXIII deficiency and comparison with older patients. Haemophilia 2014; 20: 99-105.
references: World Medical Association. Declaration of Helsinki ethical principles for medical research involving human subjects. JAMA 2013; 310: 2191-4.
references: Graf C, Battisti WP, Bridges D et al. Research Methods & Reporting. Good publication practice for communicating company sponsored medical research: the GPP2 guidelines. BMJ 2009; 339: b4330.
references: Bjorkman S. Comparative pharmacokinetics of factor VIII and recombinant factor IX: for which coagulation factors should half-life change with age? Haemophilia 2013; 19: 882-6.
references: Ajzner E, Muszbek L. Kinetic spectrophotometric factor XIII activity assays: the subtraction of plasma blank is not omissible [corrected]. J Thromb Haemost 2004; 2: 2075-7.
references: Kohler HP, Ichinose A, Seitz R, Ariens RA, Muszbek L. Diagnosis and classification of factor XIII deficiencies. J Thromb Haemost 2011; 9: 1404-6.
references: WFH Global Survey 2012. Available at http://www1.wfh.org/publications/files/pdf-1574.pdf. Accessed July 8, 2014.