title: Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study.
abstract: BACKGROUND
  Pharmacokinetic (PK) studies on recombinant FIX concentrate, Nonacog alpha, were conducted with different sampling time designs which gave rise to not complete and homogenous outcomes. In addition, patient's FIX genotype/PK relationship has never been investigated.
  
  
  OBJECTIVE
  Investigate how different sampling times may affect PK parameters and try to find a FIX genotype/PK relationship.
  
  
  METHODS
  A cohort pharmacokinetic, Nonacog Alpha single-dose, open-label, non-comparative study was conducted in eight Comprehensive Care Haemophilia Centres in Italy. Seventeen previously treated moderate or severe haemophilia B patients were enrolled. Factors IX:C one-stage clotting assay, FIX genotype and PK analysis were centralized.
  
  
  RESULTS
  The evaluation of PK outcomes showed a quite long half-life, smaller clearance and volume of distribution of Nonacog Alpha in comparison with the results from previously reported studies, where blood sampling was stopped too early. The relationship between PK outcomes and FIX genotype showed that small deletions displayed the higher clearance and shorter half-life, the nonsense mutations (the lower and the longer respectively), and missense mutations were in between.
  
  
  CONCLUSIONS
  It is evident that area under the curve (AUC) and other PK parameters depend from the sampling time design. In order to have a complete evaluation of clotting factors in vivo decay, blood samples must be collected until the baseline factor concentration has been achieved again. Due to the relationship between FIX genotype and clearance, tailored prophylaxis of HB patients could be partially predicted by genotyping.
authors.affiliation: Past President of Italian Association of Haemophilia Centres (AICE), Firenze, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Morfini
authors.affiliation: Haemophilia & Thrombosis Centre, Haematology Department, Regional Hospital, Pescara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Dragani
authors.affiliation: Atherothrombotic Diseases, Cardio-Vascular Department, University Hospital of Florence, Florence, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Paladino
authors.affiliation: Haematology and Haemophilia Centre, Regional Hospital, Castelfranco Veneto, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Radossi
authors.affiliation: Reference Centre for Haemophilia and Thrombosis, Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Di Minno
authors.affiliation: Haemophilia & Thrombosis Centre, Haematology Department, La Sapienza University, Rome, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Mazzucconi
authors.affiliation: Haemophilia Centre, Santa Chiara Hospital, Trento, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Haemophilia Centre, S. Maria della Misericordia Hospital, Udine, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barillari
authors.affiliation: Haemophilia & Thrombosis Centre, Haematology Department, University of Palermo, Palermo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: Haematology and Haemophilia Centre, Regional Hospital, Castelfranco Veneto, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tagariello
mesh_terms: D019540:Area Under Curve; D003029:Coagulants / Q000493:pharmacokinetics / Q000627:therapeutic use; D018389:Codon, Nonsense; D015331:Cohort Studies; D004334:Drug Administration Schedule; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D005838:Genotype; D006207:Half-Life; D002836:Hemophilia B / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007558:Italy; D008297:Male; D020125:Mutation, Missense; D012372:ROC Curve; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D003029:Coagulants; D018389:Codon, Nonsense; D011994:Recombinant Proteins; D005164:Factor IX
keywords: DNA Recombinant proteins; factor IX; genotype; haemophilia B; pharmacokinetics