title: Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit.
abstract: BACKGROUND
  The pharmacokinetics (PK), safety and efficacy of BAY 81-8973, a full-length, unmodified, recombinant human factor VIII (FVIII), were evaluated in the LEOPOLD trials.
  
  
  OBJECTIVE
  The aim of this study was to develop a population PK model based on pooled data from the LEOPOLD trials and to investigate the importance of including samples with FVIII levels below the limit of quantitation (BLQ) to estimate half-life.
  
  
  METHODS
  The analysis included 1535 PK observations (measured by the chromogenic assay) from 183 male patients with haemophilia A aged 1-61 years from the 3 LEOPOLD trials. The limit of quantitation was 1.5 IU dL-1for the majority of samples. Population PK models that included or excluded BLQ samples were used for FVIII half-life estimations, and simulations were performed using both estimates to explore the influence on the time below a determined FVIII threshold.
  
  
  RESULTS
  In the data set used, approximately 16.5% of samples were BLQ, which is not uncommon for FVIII PK data sets. The structural model to describe the PK of BAY 81-8973 was a two-compartment model similar to that seen for other FVIII products. If BLQ samples were excluded from the model, FVIII half-life estimations were longer compared with a model that included BLQ samples.
  
  
  CONCLUSIONS
  It is essential to assess the importance of BLQ samples when performing population PK estimates of half-life for any FVIII product. Exclusion of BLQ data from half-life estimations based on population PK models may result in an overestimation of half-life and underestimation of time under a predetermined FVIII threshold, resulting in potential underdosing of patients.
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Garmann
authors.affiliation: Model Answers Pty Ltd, Brisbane, Qld, Australia.
authors.forename: S
authors.initials: S
authors.lastname: McLeay
authors.affiliation: Bayer, Whippany, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shah
authors.affiliation: LAP&P Consultants BV, Leiden, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Vis
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Maas Enriquez
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Ploeger
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005169:Factor VIII / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007223:Infant; D057230:Limit of Detection; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011994:Recombinant Proteins / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII
keywords: clinical trials; haemophilia A; half-life estimation; population pharmacokinetics; recombinant FVIII; simulation