Human immunodeficiency virus protease inhibitors: From drug design to clinical studies

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Abstract

The discovery of human immunodeficiency virus (HIV) protease inhibitors is an example in which pharmacokinetic evaluation was implemented early in the discovery phase to obtain optimal pharmacological and pharmacokinetic properties. Currently, three HIV protease inhibitors, saquinavir, indinavir and ritonavir are clinically available. As a family, these HIV protease inhibitors are characterized pharmacologically by their ability to inhibit the viral protease enzyme. Pharmacokinetically, they are quite different due to their dissimilarity in physicochemical properties. Bioavailability appears to be limited with saquinavir, but not with indinavir and ritonavir. Although all three drugs are metabolized extensively by cytochrome P-450, saquinavir and indinavir are high clearance drugs while ritonavir is a low clearance drug. Despite their significant differences in elimination clearance, all three HIV proteases are given at high oral doses (600–800 mg) either twice or three times daily. These HIV protease inhibitors show superior therapeutic activity and a more favorable safety profile than those reported for the established reverse transcriptase inhibitors. However, the potential for interactions with other drugs metabolized by the CYP 3A4 isoform appears to be considerable. In addition, repeated administration of enzyme inducers results in a substantial decrease of plasma concentrations of protease inhibitors. Therefore, co-administration of drugs, such as rifampicin and rifabutin, must be avoided. HIV protease inhibitors are promising in the treatment of AIDS. Although they are not a cure, they can significantly inhibit that viral replication and improve the quality of life for people who have HIV infection.

Introduction

The AIDS epidemic has reached catastrophic proportions, affecting people from all socioeconomic groups around the world. According to the World Health Organization, 10 million people currently are infected by the human immunodeficiency virus (HIV), and by the year 2000, it is estimated that 25–30 million people will be infected.

Despite modest improvements in survival and delayed clinical disease progression, therapy with nucleoside analogues, such as zidovudine, didanosine and stavudine, is limited by their toxicities and rapid development of viral resistance 1, 2, 3. Therefore, there is an urgent need for new classes of antiretroviral agents which more potently inhibit viral replication, delay the emergence of viral resistance, and have less systemic toxicity.

The HIV protease enzyme is a critical component of the replicative cycle of HIV that processes polypeptides transcribed from the gag and pol genes late in the viral replicative cycle 4, 5. This process is essential for assembly and maturation of infectious virions. Inhibition of this enzyme leads to production of immature noninfectious viral progeny 5, 6. Although the HIV protease is a member of the protease family, HIV protease is unique in that it is a symmetric homodimer made up of two identical 99 amino acid residues with only one active site which is C2 symmetric [7]. Structurally, HIV protease is dissimilar to human aspartic proteases, such as renin, gastricsin and cathepsin D/E which contain only a single polypeptide chain. Due to these differences, drugs can be designed to specifically act upon viral protease without affecting mammalian proteases. Thus, the inhibition of HIV protease has attracted widespread interest for potential use in the chemotherapeutic intervention of AIDS [7].

Currently, three HIV protease inhibitors, indinavir (L-735,524; MK-0639), ritonavir (ABT-538) and saquinavir (RO-318959), are clinically available, and at least three others are under clinical investigation (Fig. 1). The purpose of this paper is to outline the role of pharmacokinetics in the drug design and review the absorption and pharmacokinetics of the clinically available HIV protease inhibitors. The data on human pharmacokinetics are limited at this time, therefore, animal data are presented to aid in characterization of the absorption, distribution and metabolism of this class of drugs.

Section snippets

Rational drug design

Historically, new lead compounds have been discovered either by serendipity or by mass screening of natural and synthetic compounds through multiple bioassays. Over the past decades, through a better understanding of disease processes, mechanism(substrate)-based drug design has evolved and produced drugs that interrupt specific biochemical pathways by targeting certain enzymes or receptors. This approach does not require a knowledge of the three-dimensional environment in which the drug is

Pharmacokinetics and absorption

HIV protease inhibitors represent a new class of antiviral agents. As a family, they are characterized pharmacologically by their ability to inhibit the viral protease enzyme. Pharmacokinetically, they are quite different due to their dissimilarity in physicochemical properties. Although all three drugs are metabolized extensively by cytochrome P-450, saquinavir and indinavir are high clearance drugs while ritonavir is a low clearance drug. Furthermore, the bioavailability appears to be limited

Plasma protein binding

The efficacy of a protease inhibitor in vivo against the virus is supposed to be related directly to its activity in vitro. Since only the unbound concentration of the protease inhibitors to which the virus are exposed counts, plasma protein binding of HIV protease inhibitors has to be taken into account in assessing their therapeutics efficacy. Conceivably, plasma protein binding could adversely affect the antiviral activity of HIV protease inhibitors. Indeed, the in vitro antiviral activity

Saquinavir

No detailed metabolism data on saquinavir have been published at the present time. Consistent with the in vivo observation of being a high clearance drug, saquinavir is metabolized rapidly in human liver microsomes. In vitro studies using human liver microsomes have shown that saquinavir is metabolized mainly by CYP 3A4 (>90%) to a range of mono- and di-hydroxylated inactive metabolites 29, 43. Furthermore, in vitro microsomal studies also have demonstrated that saquinavir is an excellent

Drug–drug interaction

Drug–drug interactions are a particular problem among immuno-compromised AIDS patients, because these patients usually require an assortment of drugs, i.e., antiretroviral agents and drugs for the treatment of a variety of infections and complications. Since metabolism represents a major route of elimination for all three HIV protease inhibitors, and since many drugs can compete for the same enzyme systems, metabolism-based drug–drug interactions between these HIV protease inhibitors and other

Conclusion

HIV protease inhibitors offer considerable promise for the clinical management of HIV infection. All of the available HIV protease inhibitors show superior therapeutic activity and a more favorable safety profile than those reported for the established reverse transcriptase inhibitors. Moreover, resistance or reduced sensitivity to the HIV protease inhibitors appears to develop much more slowly and at lower frequency even during prolonged therapy. The mutational patterns associated with

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