Amitriptyline overdose treatment by pegylated anionic liposomes

A Physiologically Based Pharmacokinetic (PBPK) Model for Predicting the Efficacy of Drug Overdose Treatment With Liposomes in Man

“…Table 2 shows that K 1 was taken to be independent of drug concentrations for TCAs and BUP. This is a reasonable assumption for TCAs across a fairly broad range of drug concentrations15–17 and for BUP within the low concentration range observed during adverse reactions (<1 µg/mL) 18. BUP concentrations are often low because overdose is not intentional as it occurs a clinical setting.…”

“…A new parameter, K eff , is defined as follows: By examining Eqs. (1) and (3), K eff can also be defined as The values of K 1 and K 2 shown in Table 2 were obtained using experimentally15–18 measured drug binding to pegylated, anionic liposomes composed of 95:5 DOPG/DPPE‐mPEG‐2000 (in mol) and serum proteins. The values of K 1 and K 2 depend linearly on the amount of protein and liposomes, respectively, in the blood.…”

“…AMI overdose was modeled as an oral dose and BUP administration was modeled as a bolus injection into the epidural space. Liposome doses were based on in vitro studies of drug binding to liposomes16–18 and were modeled as bolus IV doses. Bolus administration is a reasonable approximation because the lipid concentrations in liposome formulations79 can be as high as 50 mg/mL, allowing rapid delivery of the required amount of lipids in small fluid volumes 8, 10, 11, 80.…”

“…Amitriptyline4, 5 (AMI) and bupivacaine13, 14 (BUP) represent two of the most dangerous TCAs and local anesthetics, respectively. We previously identified anionic, pegylated liposomes capable of sequestering TCAs15–17 and BUP18 from human serum solutions with the goal of using liposome therapy to reduce toxicity through drug redistribution from vital organs to the blood compartment. While our in vitro drug binding data suggested great potential for liposome‐based overdose therapy, the in vivo efficacy could not be directly assessed.…”

“…This follows a previously published preliminary model framework and discussion concerning requirements for nanoparticles capable of treating overdoses 29. To develop the PBPK models, mechanistically based equations for tissue to blood partition coefficients developed by Rodgers et al30 were combined with in vitro drug binding data16–18 and drug specific input parameters from literature. The partition coefficients were validated by comparing model predictions to intravenous (IV) data, followed by best fits to non‐IV data to obtain first‐order absorption rate constants.…”