Nano-advantage in enhanced drug delivery with biodegradable nanoparticles: contribution of reduced clearance

Abstract

The aim of this study was to investigate the contribution of reduced apparent clearance to the enhanced exposure reported for biodegradable nanoparticles after extravascular and intravascular routes of administration. Plasma concentration profiles for drug and nanoparticle formulations after administration by intravenous, intraduodenal, and oral routes were extracted from the literature. Data were fit to pharmacokinetic models using BOOMER. The compartmental pharmacokinetic analysis of literature data for six drugs (camptothecin, 9-nitrocamptothecin, epirubicin, vinpocetine, clozapine, and cyclosporine) showed that the encapsulation of drug molecules in nanoparticles significantly reduced the apparent clearance and prolonged the apparent circulation half-life compared with those for the plain drug. Positively charged nanoparticles assessed in this study had lower apparent clearance, lower elimination rate constant values, and longer apparent circulation half-life than neutral and negatively charged nanoparticles. After oral administration, a reduction in apparent clearance contributed substantially to elevations in plasma drug exposure with nanoparticles. For the drugs and delivery systems examined, the nano-advantage in drug delivery enhancement can be explained, in part, by reduced clearance.

Fig. 1.

Model predicted and observed concentrations of camptothecin in plasma after intravenous administration in female Sprague-Dawley rats. Two-compartment model for camptothecin solution and polymer conjugated camptothecin (IT-101). kel, elimination rate constant from the plasma compartment; k12, rate constant for transfer of drug from the plasma compartment to the distribution compartment; k21, rate constant for transfer of drug from the distribution compartment to the plasma compartment.

Fig. 2.

Model predicted and observed concentrations of 9-nitocamptothecin in plasma after intravenous administration in male Wistar rats. One-compartment model for 9-nitocamptothecin solution and two-compartment model for polymeric nanoparticles of 9-nitrocamptothecin. kel, elimination rate constant from the plasma compartment; k12, rate constant for transfer of drug from the plasma compartment to the distribution compartment; k21, rate constant for transfer of drug from the distribution compartment to the plasma compartment.

Fig. 3.

Model predicted and observed concentrations of epirubicin in plasma after intravenous administration in male Wistar rats. Two-compartment model for epirubicin solution and three-compartment model for self-assembled curdlan and cholesterol nanoparticles of epirubicin. kel, elimination rate constant from the plasma compartment; k12, rate constant for transfer of drug from the plasma compartment to the distribution compartment; k21, rate constant for transfer of drug from the distribution compartment to the plasma compartment; k13, rate constant for transfer of drug from the plasma compartment to the second distribution compartment; k31, rate constant for transfer of drug from the second distribution compartment to the plasma compartment.

Fig. 4.

Model predicted and observed concentrations of vinpocetine in plasma after oral administration in male Wistar rats. One-compartment model for vinpocetine solution and two compartment model for vinpocetine solid-lipid nanoparticles. ka, absorption rate constant from GI tract to the plasma; kel, elimination rate constant from the plasma compartment; k12, rate constant for transfer of drug from the plasma compartment to the distribution compartment; k21, rate constant for transfer of drug from the distribution compartment to the plasma compartment.

Fig. 5.

Model predicted and observed concentrations of clozapine in plasma after intraduodenal (ID) and intravenous (IV) administration in male Wistar rats. Two-compartment model for clozapine suspension and clozapine solid-lipid nanoparticles. ka, absorption rate constant from GI tract to the plasma; kel, elimination rate constant from the plasma compartment; k12, rate constant for transfer of drug from the plasma compartment to the distribution compartment; k21, rate constant for transfer of drug from the distribution compartment to the plasma compartment.

Fig. 6.

Model predicted and observed concentrations of clozapine in plasma after intraduodenal and intravenous administration of nanoparticles (NP) in male Wistar rats. Two-compartment model for neutral charged solid-lipid nanoparticles and positively charged solid-lipid nanoparticles. ka, absorption rate constant from GI tract to the plasma; kel, elimination rate constant from the plasma compartment; k12, rate constant for transfer of drug from the plasma compartment to the distribution compartment; k21, rate constant for transfer of drug from the distribution compartment to the plasma compartment.

Fig. 7.

Model predicted and observed concentrations of cyclosporine in plasma after oral administration of nanoparticles (NP) in male beagle dogs. Two-compartment model for negatively charged and positively charged nanoparticles. ka, absorption rate constant from the GI tract to the plasma; kel, elimination rate constant from the plasma compartment; k12, rate constant for transfer of drug from the plasma compartment to the distribution compartment; k21, rate constant for transfer of drug from the distribution compartment to the plasma compartment.