Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 2. Colistin

Abstract

The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (VELF), a passive diffusion clearance (QELF) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg(-1)). The km was estimated to be 133 μg ml(-1), and the Vmax, in-to-Km ratio was equal to 2.5 × 10(-3) liter h(-1) kg(-1), which was 37 times higher than the QELF (6.7 × 10(-5) liter h(-1) kg(-1)). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.

FIG 1

Simultaneous PK model of plasma and ELF colistin concentrations after i.v. administration or intratracheal administration of nebulized colistin, where V_c is the volume of the central compartment, V_ELF is the fixed volume of the ELF compartment (30 μl/kg), and V_p is the volume of the peripheral compartment. CL_T corresponds to total plasma clearance, Q is the equilibrium distribution clearance between the central and peripheral compartments, and Q_ELF is the diffusion clearance between the central compartment and ELF. V_{max, in} is the maximum transfer rate from the ELF to the plasma compartment, k_m corresponds to the concentration at which the rate is half the maximum rate, and γ is the slope factor. F_aero is the systemic bioavailability after aerosol administration.

FIG 2

Predicted concentration-time profiles of colistin (0.35 mg kg⁻¹), administered i.v. and intratracheally in nebulized form, in plasma (solid line) and in ELF (dashed line) from simultaneous PK modeling. Closed and open symbols represent mean ± SD values for experimental concentrations in total plasma and in ELF, respectively. *, BAL drug concentrations after i.v. administration were below the limit of quantification and ELF concentrations could not be estimated.

FIG 3

Predicted concentration-time profiles of colistin administered intratracheally in nebulized form at a dose of 0.035 mg kg⁻¹ in plasma (solid line) and in ELF (dashed line) from simultaneous PK modeling. Closed and open symbols represent mean ± SD of experimental concentrations in total plasma and in ELF, respectively.