Predicting Inter-individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study

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.