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Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin

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Abstract

Purpose

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.

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Abbreviations

ACS:

Acute coronary syndrome

aPTT:

Activated partial thromboplastin time

AT:

Antithrombin

BSV:

Between subject variability

CT:

Clotting time

DVT:

Deep vein thrombosis

LMWH:

Low molecular weight heparin

PE:

Pulmonary embolism

PT:

Prothrombin time

RE:

Relative error

TenaCT:

Ten-a clotting time

TT:

Thrombin time

UFH:

Unfractionated heparin

VTE:

Venous thromboembolism

g :

Unit of acceleration

j :

Index for a parameter

J :

Jacobian matrix

k :

Index for iteration

K D :

Affinity constant

M F :

Fisher information matrix

|M F (⋅)|:

Determinant of the Fisher information matrix

p :

Total number of parameters

T:

Transpose

U :

Utility function

ξ 0 :

Initial design

ξ * D :

D-optimal design

ξ * DP :

DP-optimal design

β :

Any parameter in a model

\( \widehat{\beta} \) :

Estimate of any parameter in a model

\( \overline{\beta} \) :

Mean of any parameter in a model

β :

Vector of parameters in the model

\( \widehat{\boldsymbol{\upbeta}} \) :

Vector of the estimated parameters

Σ :

Covariance of the residual error

References

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors acknowledge the support of University of Otago Postgraduate Scholarship and the University of Otago Research Grant 2011.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, Indiana University School of Medicine, R2 Building, 950 West Walnut Avenue, 4th Floor, Room E471, Indianapolis, Indiana, 46202, USA

    Abhishek Gulati

  2. School of Pharmacy, University of Otago, Dunedin, New Zealand

    Abhishek Gulati & Stephen B. Duffull

  3. Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand

    James M. Faed

  4. School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia

    Geoffrey K. Isbister

Authors
  1. Abhishek Gulati
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  2. James M. Faed
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  3. Geoffrey K. Isbister
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  4. Stephen B. Duffull
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Corresponding author

Correspondence to Abhishek Gulati.

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Gulati, A., Faed, J.M., Isbister, G.K. et al. Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin. Pharm Res 32, 3391–3402 (2015). https://doi.org/10.1007/s11095-015-1715-1

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  • DOI: https://doi.org/10.1007/s11095-015-1715-1

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