Encouraging the move towards predictive population models for the obese using propofol as a motivating example

McLeay, Sarah C., Morrish, Glynn A., Kirkpatrick, Carl M. and Green, Bruce (2009) Encouraging the move towards predictive population models for the obese using propofol as a motivating example. Pharmaceutical Research, 26 7: 1626-1634. doi:10.1007/s11095-009-9873-7


Author McLeay, Sarah C.
Morrish, Glynn A.
Kirkpatrick, Carl M.
Green, Bruce
Title Encouraging the move towards predictive population models for the obese using propofol as a motivating example
Journal name Pharmaceutical Research   Check publisher's open access policy
ISSN 0724-8741
1573-904X
Publication date 2009-01-01
Sub-type Article (original research)
DOI 10.1007/s11095-009-9873-7
Open Access Status
Volume 26
Issue 7
Start page 1626
End page 1634
Total pages 9
Editor V. H. L. Lee
Place of publication United States
Publisher Springer New York LLC
Language eng
Subject C1
920111 Nervous System and Disorders
111502 Clinical Pharmacology and Therapeutics
Abstract Purpose To develop a predictive pharmacokinetic model for propofol that could inform development of a dosing strategy for the obese population. Methods A prior model that included a nonlinear relationship between clearance (CL) and Total Body Weight (TBW) was re-parameterized with a linear relationship between CL and Lean Body Weight (LBW). The predictive performance of both models was compared and the LBW model used to explore propofol exposure from normal to obese patients. A dosing strategy was evaluated that normalized awakening time across a range of patient weights. Results The predictive performance of the LBW model was similar to the nonlinear TBW model for normal weighted subjects. Simulations in 70–160 kg subjects indicated that dosing linearly on TBW (label recommendation), in contrast to LBW, resulted in increased plasma concentrations in the larger weight groups. This result might explain why obese subjects take longer to awaken from anesthesia compared to normal weighted subjects. Dosing by LBW normalized patient awakening times across this weight range. Conclusions LBW as a covariate provides a plausible mechanistic explanation for an observed nonlinear increase in drug CL with TBW and may be suitable for developing dosing strategies that are appropriate for use in the obese population.
Keyword lean body weight
propofol
population pharmacokinetics
obesity
mechanistic covariates
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Pharmacy Publications
 
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Created: Fri, 31 Jul 2009, 22:25:51 EST by Charna Kovacevic on behalf of School of Pharmacy