title: Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin.
abstract: OBJECTIVE
  Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study.
  
  
  METHODS
  A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP-optimality.
  
  
  RESULTS
  The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of-concept study.
  
  
  CONCLUSIONS
  This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, R2 Building, 950 West Walnut Avenue, 4th Floor, Room E471, Indianapolis, Indiana, 46202, USA. agulati@iu.edu.|School of Pharmacy, University of Otago, Dunedin, New Zealand. agulati@iu.edu.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gulati
authors.affiliation: Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: James M
authors.initials: JM
authors.lastname: Faed
authors.affiliation: School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Isbister
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Duffull
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests / Q000379:methods; D017984:Enoxaparin / Q000627:therapeutic use*; D065427:Factor Xa Inhibitors / Q000627:therapeutic use; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D012107:Research Design; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D065427:Factor Xa Inhibitors
keywords: Adaptive design; DP-optimal design; Response surface modelling; enoxaparin; factor Xa