(348d) A Physiologically Based Pharmacokinetic (PBPK) Model for Evaluating the Efficacy of Liposomes at Treating Tricyclic Antidepressant or Local Anesthetic Overdoses

Many drugs such as tricyclic antidepressants (TCA) and local anesthetics cause severe toxicity and/or death when taken at excessive and sometimes normal dosage levels. This study focuses on the use of physiologically based pharmacokinetic (PBPK) models for the development and optimization of liposomes for drug overdose treatment.

We have performed a series of in vitro binding studies using pegylated, anionic liposomes as drug sequestering agents. Drug affinities for various types and loadings of liposomes, as well as serum proteins, were quantified. PBPK models were then developed for predicting the efficacy of liposomes at overdose treatment in humans. Organ to blood partition coefficients for the drugs were calculated using published mechanistic equations. Hepatic extraction and renal elimination were obtained from previously published pharmacokinetic studies. Intravenous human data from various sources was compared to model predictions to serve as model validation. First order absorption was assumed and absorption rate constants for the oral absorption of antidepressants and non-oral absorption from the epidural, intercostal, or intraperitoneal spaces for anesthetics were obtained by best fits to published human studies. Thus, PBPK models capable of accurate drug concentration predictions in all tissues were constructed without the need for additional animal or human studies.

A series of overdose cases were then simulated with variations in drug and liposome dose, elapsed time between drug intake and liposome treatment, and patient specific input parameters. A single dose of the pegylated, anionic liposomes was predicted to be highly effective at treating antidepressant overdoses. A bolus dose of 1.44 g liposomes/L blood 2 hours after overdose reduced the area under the amitriptyline concentration curves (AUC) by 64% for the heart and brain. Heart and brain drug concentration peaks were predicted to drop by 20.1% and 20%, respectively. Although liposomes could potentially treat an anesthetic overdose, the drug redistribution was less effective, with bupivacaine AUC decreases of 15.4% and 15.3% for the heart and brain, respectively. Bupivacaine peak concentration reductions for both the heart and brain were 17.3%. Liposome doses were also increased twofold (2.88 g lipid/L blood as a single dose) to achieve such reductions for bupivacaine and the liposomes were assumed to be injected 15 minutes after the overdose.

The increased lipophilicity and proportion of molecules in the charged state at the physiological pH of 7.4 for antidepressants when compared to anesthetics, as well as their molecular structures, make them more susceptible to liposome sequestration. Nonetheless, the PBPK model showed that both antidepressant and local anesthetic overdoses may be successfully treated with liposome sequestration, with required doses drastically reduced compared to lipid emulsions currently used for local anesthetic overdose treatment. The predicted pharmacokinetic behavior after liposome administration was in reasonable agreement with available pharmacokinetic data from clinical studies where particles such as protein fragments were administered to patients for overdose treatment. Published data on ion channel function was used to connect the predicted concentrations in the body to local pharmacodynamic effects in the heart.