Abstract

Purpose: To fit an absorption-pharmacokinetic model for simulation of tobramycin in adult and pediatric populations.

Methods: Tobramycin pulmonary absorption and pharmacokinetics were simulated using GastroPlus™ 7.0 (Simulations Plus, Inc., Lancaster, CA). Tobramycin pharmacokinetics was simulated with a physiologically-based pharmacokinetic (PBPK) model with all permeability limited tissues. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™. Tissue/plasma partition coefficients (Kp’s) were calculated using Poulin’s equation for drug partitioning into extracellular space [1] from in vitro and in silico physicochemical properties (ADMET Predictor™ 5.0, Simulations Plus, Lancaster, CA). Single specific permeability-surface area product (PStc per mL tissue) was fitted against in vivo plasma concentration-time (Cp-time) data after i.v administration of tobramycin in adults with impaired renal function. The total PStcs for individual tissues were calculated as a product of the specific PStc and the total cell volume of each tissue. Renal clearance was fitted against Cp-time profile after i.v. administration of tobramycin in adults with normal renal function. The pulmonary component of the GastroPlus Additional Dosage Routes Module™ was used to model the pulmonary absorption. The deposition fractions for two formulations were used as reported in literature [2]. Pulmonary permeability was fitted against Cp-time profiles after pulmonary administration of a PulmoSphere (solid particulate) formulation of tobramycin in adults and validated by using the model to predict the Cp-time profile in adults after pulmonary administration of a TOBI (nebulizer) formulation. The same model (fitted against adult in vivo data) was then used to predict tobramycin pharmacokinetics after i.v. and pulmonary administration in children.

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