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

Howell, Brett A.; Chauhan, Anuj

doi:10.1002/jps.22115

Cited by 20 publications

(21 citation statements)

References 89 publications

(234 reference statements)

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“…Such loading was anticipated to produce a whole blood lipid concentration approximating 0.8 mg/mL, in line with the in vitro work and human modeling described by Howell and Chauhan. 10 All treatments were warmed to 37°C prior to infusion.…”

Section: Study Protocolmentioning

confidence: 99%

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Cave

Harvey

Shaw

et al. 2013

Academic Emergency Medicine

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Objectives: Liposome (LIP)-like lipid dispersions have emerged as useful detoxification vehicles in vitro. The authors compare resuscitation with tailored LIPs, 20% intravenous lipid emulsion (ILE), and sodium bicarbonate (BIC), in a rabbit model of clomipramine toxicity.Methods: Sedated, instrumented New Zealand white rabbits underwent clomipramine infusion at 3.2 mg/kg/min to 50% baseline mean arterial pressure (MAP) and then at 1.6 mg/kg/min for 30 minutes. BIC (3 mL/kg 8.4%), ILE (3 mL/kg 20%), or LIP (24 mg/kg) were infused as rescue treatments at toxicity and were repeated at 10 minutes (n = 5 in each group). remains a difficult therapeutic challenge. Mainstays of therapy include aggressive supportive care and sodium bicarbonate (BIC)-initiated systemic alkalinization. 1 More recently, intravenous lipid emulsion (ILE) preparations have been forwarded as adjuncts to standard management of TCA toxicity with successful reports of use in animal models 2 and human subjects. 3 Both pharmacokinetic and pharmacodynamic mechanisms have been forwarded to explain the beneficial effects of ILE. The widely held lipid sink theory is that lipid sequesters certain xenobiotics (such as TCAs) and reduces toxicity by decreasing the free serum concentration of the offending toxin. 4,5 Liposomes are spherical vesicles of phospholipids and effectively sequester amitriptyline and imipramine in vitro. 6,7 Specific advantages afforded by liposomes (LIPs) include increased surface area:volume ratios, the ability to modulate surface charge and internal pH, and the inherent lipid bilayer structure. To date, however, there are limited data on the antidotal efficacy of liposomal formulations in intact animal models.We examined the effect of LIPs in an established animal model of TCA toxicity. Specifically, in this study we compare resuscitation with bicarbonate (BIC), ILE, and LIPs in a previously studied rabbit model of clomipramineinduced shock. METHODS Study DesignThis was a laboratory study of clomipramine-induced cardiotoxicity in a rabbit model. The study was approved by the institutional ethics committee of the

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Section: Study Protocolmentioning

confidence: 99%

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Cave

Harvey

Shaw

et al. 2013

Academic Emergency Medicine

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“…In the past, WB-PBPK model had been considered difficult to parameterize because of the requirement for measurements of tissue-to-plasma partition coefficient (K p ) for each organ. Experiments for obtaining K ps are usually difficult and labor-intensive and also require conducting numerous animal studies to ensure accuracy [60] . Moreover, many tissues are generally omitted due to practical limitations.…”

Section: Discussionmentioning

confidence: 99%

Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

Wang

Chen

et al. 2012

Acta Pharmacol Sin

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Aim: To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment. Methods: Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composi tionequationsanddrug-specificpropertiessuchaslogP,permeability,andplasmaproteinbindingpublishedinliteratures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methodsfollowedbyincorpora tionintotheWB-PBPKmodel.Modelrefinementswereconductedafteracomparisonofthesimulated concentration-timeprofilesandpharmacokineticparameterswiththeobserveddatainhealthyadultsfollowingintravenousandoral administration. Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients. Results: The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters (AUC, C max , and T max ) were reasonably consistent(<1.3-folderror)withtheobservedvaluesaftersingleoraladministrationofdosesrangingfromof5to20mgusingtherefined WB-PBPKmodel.Thesimulatedplasmaprofilesaftermultipleoraladministrationofbisoprololinhealthyadultsandpatientwithrenal impairmentmatchedwellwiththeobservedprofiles. Conclusion:The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multi ple dose levelsindiversenormaladulthumanpopulationsandpatientswithrenalinsufficiency.

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“…Basic science experimentation is furthermore required to delineate optimal doses and formulations of ILE for human application. Research exploring the utility of liposomal detoxification vesicles has proven informative, with engineered liposomes demonstrating ability to sequester lipophilic toxins with far greater affinity than standard ILE in vitro [ 70 ]. Subsequent use in animal models has shown the ability of such formulations to effect meaningful recovery [ 71 ].…”

Section: Future Researchmentioning

confidence: 99%

Should we consider the infusion of lipid emulsion in the resuscitation of poisoned patients?

Cave

Harvey

2014

Crit Care

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The use of intravenous lipid emulsions (ILEs) as antidote in local anaesthetic systemic toxicity has gained widespread support following convincing data from animal models, and successful case reports in humans. Proposed beneficial mechanisms of action for ILEs include intravascular sequestration of intoxicant and subsequent enhanced redistribution to biologically inert tissues, augmentation of fatty acid utilisation for ATP synthesis in the context of metabolic poisoning, and direct cardiotonic and ion channel effects. The evidence base for use of ILEs in acute drug intoxication is evolving. The present evidence supports use of ILEs only in local anaesthetic systemic toxicity and in lipophilic cardiotoxin intoxication when there is an immediate threat to life, and other therapies have proven ineffective.

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

Cited by 20 publications

References 89 publications

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

Should we consider the infusion of lipid emulsion in the resuscitation of poisoned patients?

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