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

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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. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:680–689, 2002

Section snippets

INTRODUCTION

Ritnavir (RIT), nelfinavir (NEL) saquinavir (SAQ), indinavir (IND) and amprenavir (AMP) are all potent HIV-protease inhibitors that have been used for the treatment of patients with advanced acquired immune deficiency syndrome (AIDS) in clinical practice. Recently, a combination therapy with two kinds of reverse transcriptase inhibitors and an HIV protease inhivitor, namely highly active anti-retrovial therapy, has significantly delayed the progression of HIV-related disease and prolonged

Chemicals and Standard Solutions

Amprenavir (AMP), saquinavir (SAQ) and indinavir (IND) were kindly supplied from Vertex Pharmaceuticals Inc. (Cambridge, MA), Hoffman-LaRoche Inc. (Nutley, NJ), and Merck Sharp & Dohme Research Laboratories (Rahway, NJ), respectively. Nelfinavir (NEL) and ritnavir (RIT) were extracted from capsules commercially available, and were purified by preparative HPLC method. HCO-40 and PharmasolveR to prepare a solution of injection were kindly supplied by Nikko Chemicals (Tokyo, Japan) and ISP

RESULTS AND DISCUSSION

In the previous reports, 10 to 14 tissues and organs were involved in the PB-PK models.24., 25., 26. In this study, a PB-PK model to estimate pharmacokinetic interaction among HIV protease inhibitors was constructed with three compartments comprising the liver, intestine, and other organ (which were considered the sum of organs except for liver and intestine), and the RB values of the drugs were used to link those three compartments. Although actual levels of drugs in tissue compartment could

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    Copyright © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association. Published by Elsevier Inc. All rights reserved.