Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model

Abstract

A Physiologically-based pharmacokinetic (PB-PK) model was developed to describe the aspects of pharmacokinetic interactions between five HIV protease inhibitors (ritonavir, amprenavir, nelfinavir, saquinavir, indinavir) in rats. To increase usefulness of this BP-PK model, liver, intestinal tissue and other organ were assumed as compartments in this model. Each compartment was linked with the blood flow and the blood-to-plasma concentration ratios of those drugs, and the absorption process in the intestinal tract was presumed as a first-order kinetics. In addition, this PB-PK model incorporates two elimination processes due to hepatic and intestinal metabolism constructed by in vitro metabolic clearance rates and inhibition constants between HIV protease inhibitors. Excellent agreements were obtained between the predicted and observed concentrations of HIV protease inhibitors in rat plasma after a 20 mg/kg oral dose or co-administration of two kinds of HIV protease inhibitors (amprenavir/indinavir, nelfinavir/amprenavir, saquinavir/amprenavir, amprenavir/ritonavir, indinavir/ritonavir, nelfinavir/ritonavir, and saquinavir/ritonavir) with each 20 mg/kg oral dose. However, underestimates in the predicted plasma concentrations of saquinavir, indinavir and amprenavir were observed during the terminal phase after co-administration with ritonavir or amprenavir, suggesting that a term of other inhibitory process, such as a mechanism-based inhibition, might be incorporated into this PB-PK model. This BP-PK model enables us to know useful information about pharmacokinetic interaction when HIV infected patients would receive double protease therapy.