title: Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint.
abstract: OBJECTIVE
  In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters.
  
  
  METHODS
  Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM.
  
  
  RESULTS
  In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)).
  
  
  CONCLUSIONS
  A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Diepstraten
authors.forename: Esther J H
authors.initials: EJ
authors.lastname: Janssen
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hackeng
authors.forename: Eric P A
authors.initials: EP
authors.lastname: van Dongen
authors.forename: René J
authors.initials: RJ
authors.lastname: Wiezer
authors.forename: Bert
authors.initials: B
authors.lastname: van Ramshorst
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D065427:Factor Xa Inhibitors / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017762:Nadroparin / Q000494:pharmacology*; D009767:Obesity, Morbid / Q000097:blood*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D017762:Nadroparin