title: Leveraging physiological data from literature into a pharmacokinetic model to support informative clinical study design in pregnant women.
abstract: OBJECTIVE
  Physiological changes during pregnancy can effect pharmacokinetic (PK) parameters, which may lead to altered dose requirements. We aimed to leverage literature-based physiological changes during pregnancy into a PK model and compare its performance to a published reference model in pregnant women and to use the literature-based model to determine informative PK sampling times for a clinical study that aims to quantify the PK of enoxaparin throughout pregnancy.
  
  
  METHODS
  Changes in total body water (BW) and creatinine clearance (CRCL) during pregnancy were described using regression models. BW and CRCL were linked to a PK model of enoxaparin in non-pregnant women. Performance of the literature-based PK model was compared to a previously published empirical reference model. D-optimal sampling times were determined and evaluated for literature-based and reference models.
  
  
  RESULTS
  The literature-based model adequately predicted anti-Xa plasma concentrations when compared to reference model predictions. An informative sampling design was successfully developed, with parameters expected with good precision (RSE < 36.4%).
  
  
  CONCLUSIONS
  A literature-based model describing enoxaparin PK during pregnancy was developed and evaluated. The modelling framework could be used to support development of informative designs in pregnancy when prior models are unavailable.
authors.affiliation: Department of Pharmacy and Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands. jgc.vanhasselt@gmail.com
authors.forename: J G Coen
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: Bruce
authors.initials: B
authors.lastname: Green
authors.forename: Glynn A
authors.initials: GA
authors.lastname: Morrish
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D001834:Body Water / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016903:Drug Monitoring / Q000379:methods; D017984:Enoxaparin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065427:Factor Xa Inhibitors; D005260:Female; D005865:Gestational Age; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011247:Pregnancy; D015203:Reproducibility of Results
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D003404:Creatinine