Journal article
M. McDaniel, K. Flores, B. Akpa
Drugs in R&D, 2021
Drugs in R&D, 2021
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APA
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McDaniel, M., Flores, K., & Akpa, B. (2021). Predicting Inter-individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study. Drugs in R&Amp;D.
Chicago/Turabian
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McDaniel, M., K. Flores, and B. Akpa. “Predicting Inter-Individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study.” Drugs in R&D (2021).
MLA
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McDaniel, M., et al. “Predicting Inter-Individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study.” Drugs in R&Amp;D, 2021.
BibTeX Click to copy
@article{m2021a,
title = {Predicting Inter-individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study},
year = {2021},
journal = {Drugs in R&D},
author = {McDaniel, M. and Flores, K. and Akpa, B.}
}
Abstract
Introduction
Intravenous lipid emulsions (ILE) have been credited for successful resuscitation in drug intoxication cases where other cardiac life-support methods have failed. However, inter-individual variability can function as a confounder that challenges our ability to define the scope of efficacy for lipid interventions, particularly as relevant data are scarce. To address this challenge, we developed a quantitative systems pharmacology model to predict outcome variability and shed light on causal mechanisms in a virtual population of rats subjected to bupivacaine toxicity and ILE intervention.
Materials and Methods
We combined a physiologically based pharmacokinetic–pharmacodynamic model with data from a small study in Sprague-Dawley rats to characterize individual-specific cardiac responses to lipid infusion. We used the resulting individual parameter estimates to posit a population distribution of responses to lipid infusion. On that basis, we constructed a large virtual population of rats (N = 10,000) undergoing lipid therapy following bupivacaine cardiotoxicity.
Results
Using unsupervised clustering to assign resuscitation endpoints, our simulations predicted that treatment with a 30% lipid emulsion increases bupivacaine median lethal dose (LD50) by 46% when compared with a simulated control fluid. Prior experimental findings indicated an LD50 increase of 48%. Causal analysis of the population data suggested that muscle accumulation rather than liver accumulation of bupivacaine drives survival outcomes.
Conclusion
Our results represent a successful prediction of complex, dynamic physiological outcomes over a virtual population. Despite being informed by very limited data, our mechanistic model predicted a plausible range of treatment outcomes that accurately predicts changes in LD50 when extrapolated to putatively toxic doses of bupivacaine. Furthermore, causal analysis of the predicted survival outcomes indicated a critical synergy between scavenging and direct cardiotonic mechanisms of ILE action.