title: Low-molecular-weight heparin pharmacokinetics: a dual absorption model approach.
abstract: OBJECTIVE
  The aim of this study was to develop a novel population pharmacokinetic (PPK) model of dalteparin after subcutaneous (s.c.) injection, to describe the impact of the "flip-flop" phenomenon and to demonstrate any ethnic difference between Asian and Caucasian subjects.
  
  
  METHODS
  The PPK model was constructed based on data collected from Asian (Japanese) and Caucasian (French) subjects with a total of 931 plasma anti-Xa activity measurements. After s.c. injection, the apparent elimination half-life of the dalteparin was about 4 hours, longer than that reported after intravenous (i.v.) injection, indicating a "flip-flop" phenomenon. In addition, following the mono-exponential decline profile after s.c. injection, a longer secondary phase was apparently observed in 70% of subjects. To investigate the phenomenon, we applied a dual absorption model including fast first-order and slow zero-order inputs as the structural model.
  
  
  RESULTS
  The PPK model for s.c. injection provided the half-life consistent with that of i.v. injection and could account for the observed bi-phasic profile. Body weight and gender for clearance and body weight for volume of distribution were identified as covariates. Due to lower body weight in Asian subjects, an ethnic difference might occur but it would not be reflected by per kg body weight injection.
  
  
  CONCLUSIONS
  Dalteparin PK profiles after s.c. injection were described reasonably by the novel PPK model based on flip-flop pharmacokinetics and a dual absorption process.
authors.affiliation: Clinical Pharmacology, Global Research & Development, Tokyo Laboratories, Pfizer, Japan.
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Abe
authors.forename: Koji
authors.initials: K
authors.lastname: Chiba
authors.forename: Toshio
authors.initials: T
authors.lastname: Suwa
mesh_terms: D000042:Absorption; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D044466:Asian People; D001835:Body Weight; D018592:Cross-Over Studies; D017985:Dalteparin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005260:Female; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D008970:Molecular Weight; D016037:Single-Blind Method; D013997:Time Factors; D044465:White People; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D017985:Dalteparin