Application of a Respiratory PBPK Model for Predicting Deposition and Disposition following Inhaled Administration of Morphine

Conference: AAPS
Software: GastroPlus®
Division: Simulations Plus


Objective: Demonstrate the pulmonary component of the GastroPlus™ Additional Dosage Routes Module™ (ADRM) simulation to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for inhaled administration of morphine in humans.

Methodology: The GastroPlus pulmonary model, shown in Figure 1, has been used in earlier studies2-4. The model accounts for:

  • mucociliary transit
  • dissolution/ precipitation
  • absorption into pulmonary cells
  • non-specific binding in mucus/ surfactant layers and cells
  • (linear) metabolism
  • transfer into the systemic circulation
  • partial swallowing of the inhaled dose

Swallowed portions of the inhaled dose have been accounted for using the Advanced Compartmental Absorption and Transit (ACAT™) model within GastroPlus. Human lung physiological parameters (surface area, thickness and volume for the mucus and cell) for each compartment were obtained from the literature5-7. Three-compartment PK parameters were fitted to observed Cp–time profiles from a 7-minute 8.8 mg i.v. infusion dose in healthy human subjects8 using the PKPlus™ module within GastroPlus. Physicochemical properties were obtained from in vitro measurements9 or in silico predictions10. Pulmonary permeability and systemic absorption rate was adjusted against the reported in vivo inhaled data. Fixed liver first-pass extraction (76.2%)11 was used in all simulations. Deposition fractions in the lung compartments were calculated both by the built-in ICRP 665 algorithm and an external Multiple Path Particle Dosimetry (MPPD) Model12 assuming complete mouth breathing. Particle diameter of 2.96 μm with a geometric standard deviation of 1.24 μm, reported for AERx devices13, was used to calculate deposition fractions, with an airflow rate of 73 L/min8. Observed pharmacodynamic (PD) data for pupil diameter was fitted to the PK model using the PDPlus™ module of GastroPlus.

American Association of Pharmaceutical Scientists (AAPS), November 14-18, 2010, New Orleans, LA

By S. Ray Chaudhuri, Viera Lukacova, Walter S. Woltosz