Physiologically-based pharmacokinetic (PBPK) model for prediction of midazolam pharmacokinetics after intranasal administration in children
Poster Jun 07, 2012
Viera Lukacova,Siladitya Ray Chaudhuri, Walter S. Woltosz , Michael B. Bolger
Purpose: To predict midazolam absorption and pharmacokinetics (PK) after intranasal (i.n.) administration in young children.
Methods: The absorption and PK of midazolam were simulated using GastroPlusTM7.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental Absorption and Transit (ACATTM) model described the intestinal absorption and gut first pass extraction (FPE) for oral (p.o.) doses, coupled with its PBPKPlusTMmodule for simulation of the PK distribution, liver FPE and systemic clearance, and its Additional Dosage Routes Module (ADRMTM) for simulation of absorption after i.n.administration. The accuracy of the ACAT model simulations for midazolam in healthy adult volunteers was previously validated by comparing the simulated plasma concentration-time profiles with experimental profiles after intravenous (i.v.) and p.o.administration. The ADRM module within GastroPlus was used to simulate the absorption after i.n.administration in healthy adults and in children (average age 2 years). Built-in age-dependent physiologies of the respiratory system were used to describe nasal absorption in both populations. The initial deposition of the drug was assumed to be 100% in the nose. The permeability through nasal mucosa and systemic absorption rate were fitted to in vivodata after i.n.administration in adults and, without further adjustments, were used to predict the absorption of midazolam after i.n.administration in children.
Results : This PBPK model, when coupled with age-dependent gastrointestinal and respiratory physiologies, was able to account for differences in the absorption and disposition of midazolam between adults and children and resulted in accurate predictions of midazolam exposure after i.n.administration in children.
Conclusions: Successful predictions of midazolam disposition in children after i.v. andp.o.administration were previously reported. The current study validates the utility of a physiologically-based approach for prediction of midazolam disposition in children after an alternative route of administration.
Human iPSC-derived cardiomyocytes: A translational model to predict drug-induced cardiac arrhythmias and long-term toxicityPoster
The results shown here imply that iPSC-derived Cor.4U human cardioymocytes are a translational in vitro cell model for the prediction of clinically relevant drug-induced cardiac arrhythmias and long-term toxicity.READ MORE
Bioluminescent Kinase Profiling Systems For Characterizing Small Molecule Kinase InhibitorsPoster
In order to profile compounds against a broad panel of kinases, in-house profiling requires rigorous kinase assay development.READ MORE
Assessment of Oral LISPRO Treatment in Ameliorating Amyloid and Tau Pathology in Transgenic Alzheimer’s Mice ModelPoster
Ionic co-crystals of lithium salicylate with organic proline (LISPRO) showed better safety and pharmacokinetic profile of lithium in plasma and brain of wild-type and transgenic Alzheimer mice model compared to lithium salts.READ MORE