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Leveraging Physiological Data from Literature into a Pharmacokinetic Model to Support Informative Clinical Study Design in Pregnant Women

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Abstract

Purpose

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 succesfully developed, with parameters expected with good precision (RSE < 36.4%).

Conclusion

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.

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Abbreviations

BW:

body water

BW0 :

pre-pregnancy body water

BWMAX :

maximum change in body water

BW50 :

half-maximum change in body water

BWγ :

Hill coefficient for body water

CL:

clearance

CLNP :

non-pregnant clearance

CLNR :

non-renal clearance

CLR :

renal clearance

CRCL:

creatinine clearance

CRCL0 :

non-pregnant creatinine clearnace

CRCLMAX :

maximum change in creatinine clarance

CRCL50 :

half-maximum change in creatinine clearance

f e :

fraction of renal clearance

IU:

international units

PD:

pharmacodynamics

PK:

pharmacokinetics

RSE:

relative standard error

RUV:

residual unexplained variability

SCR:

serum creatinine

V:

volume

VNP :

non-pregnant volume of distribution

WT:

body weight

WT0:

pre-pregnancy body weight

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands

    J. G. Coen van Hasselt

  2. Model Answers Pty Ltd., Brisbane, Australia

    Bruce Green & Glynn A. Morrish

  3. Goodness of Fit Pty Ltd., Brisbane, Australia

    Glynn A. Morrish

  4. School of Pharmacy, University of Queensland, Brisbane, Australia

    J. G. Coen van Hasselt

  5. School of Medicine, University of Queensland – Mater Clinical School, Brisbane, Australia

    Bruce Green

Authors
  1. J. G. Coen van Hasselt
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  2. Bruce Green
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  3. Glynn A. Morrish
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Corresponding author

Correspondence to J. G. Coen van Hasselt.

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van Hasselt, J.G.C., Green, B. & Morrish, G.A. Leveraging Physiological Data from Literature into a Pharmacokinetic Model to Support Informative Clinical Study Design in Pregnant Women. Pharm Res 29, 1609–1617 (2012). https://doi.org/10.1007/s11095-012-0671-2

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  • DOI: https://doi.org/10.1007/s11095-012-0671-2

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