title: Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis.
abstract: BACKGROUND
  We previously showed that pharmacokinetic-guided prophylaxis (PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII (FVIII) levels and area under the curve (AUC) with breakthrough bleeding have not been investigated.
  
  
  OBJECTIVE
  The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis.
  
  
  METHODS
  Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP.
  
  
  RESULTS
  During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL(-1) , with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding (P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL(-1) was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h.
  
  
  CONCLUSIONS
  When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL(-1) provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens.
authors.affiliation: Baxalta US Inc., Deerfield, IL, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Valentino
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Pipe
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: P W
authors.initials: PW
authors.lastname: Collins
authors.affiliation: Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: V S
authors.initials: VS
authors.lastname: Blanchette
authors.affiliation: Lund University, Skane University Hospital, Malmö, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Berntorp
authors.affiliation: Van Creveldkliniek, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Baxter Healthcare Corporation, Westlake Village, CA, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Ewenstein
authors.affiliation: Baxter Healthcare Corporation, Westlake Village, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Oh
authors.affiliation: Baxter Healthcare Corporation, Westlake Village, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Spotts
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002648:Child; D003029:Coagulants / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005169:Factor VIII / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy* / Q000473:pathology; D006470:Hemorrhage / Q000517:prevention & control*; D006801:Humans; D007596:Joints; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D012306:Risk; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D003029:Coagulants; D005169:Factor VIII
keywords: bleeding; haemarthrosis; haemophilia; joint bleeding; pharmacokinetic-guided treatment; prophylaxis; rAHF-PFM