Abstract

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 GastroPlus™ 7.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental Absorption and Transit (ACAT™) model described the intestinal absorption and gut first pass extraction (FPE) for oral (p.o.) doses, coupled with its PBPKPlus™ module 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 vivo data after i.n. administration in adults and, without further adjustments, were used to predict the absorption of midazolam after i.n. administration in children.

American Association of Pharmaceutical Scientists (AAPS), October 23-27, 2011, Washington, D.C.

By Viera Lukacova, Siladitya Ray Chaudhuri, Walter S. Woltosz , Michael B. Bolger