Oral absorption of the HIV protease inhibitors: a current update
Introduction
The human immunodeficiency virus (HIV) protease inhibitors are a novel class of drugs that potently inhibit viral replication and are considered the most important therapeutic agents to date for the treatment of HIV infection [1], [2]. HIV protease inhibitors in combination with nucleoside reverse transcriptase inhibitors are recommended as initial treatment for all HIV infected patients due to their efficacy in viral suppression and in reducing morbidity and mortality among patients [2], [3], [4].
There are currently four marketed HIV protease inhibitors in the United States: saquinavir mesylate (Invirase®, 200 mg base/hard gelatin capsule, Roche Laboratories), ritonavir (Norvir™, 100 mg hard gelatin capsules and 80 mg/ml oral solution, Abbott Laboratories), indinavir sulfate (Crixivan®, 200 mg and 400 mg base/hard gelatin capsules, Merck) and nelfinavir mesylate (Viracept® 250 mg base/tablet and 50 mg base/g oral powder, Agouron). Saquinavir was approved first in December 1995. Ritonavir and indinavir were approved in March 1996, with nelfinavir being approved in March 1997 [1]. A second saquinavir dosage form, Fortovase™, a 200 mg soft gelatin capsule containing saquinavir base was approved in November 1997. Fortovase™ has improved bioavailability relative to Invirase® [5]. An NDA for amprenavir mesylate (Agenerase, 150 mg tablets, Glaxo Wellcome) was recently submitted and is currently awaiting FDA approval. Although there are many potential new drugs in development, this review will focus on the five aforementioned drugs for which the most published data exist. Being relatively new drugs, however, in some cases the published data are limited. There have also been a number of cases where conflicting or incomplete data have been reported.
HIV protease is classified as an aspartic protease and is essential for the production of infectious virions. During the late stages of the HIV replication cycle, the viral gag and gag-pol polypeptides combine with two molecules of viral RNA and envelope proteins to form immature virus particles. Viral protease then cleaves the gag and gag-pol polypeptides to form mature virus particles that can recognize and infect other target cells. Inhibiting viral protease leads to the release of immature, noninfectious, virions that halt the spread of virus to uninfected cells. Inhibitors of HIV protease do not effect mammalian proteases due to the dissimilarity of HIV protease and the human aspartic proteases (e.g. renin) [6], [7], [8], [9].
The five aforementioned HIV protease inhibitors are structurally related peptidomimetics (Fig. 1) and possess a hydroxyethylamine functionality that acts as a transition-state intermediate inhibitor in the active site of the HIV protease [7], [9]. Collectively, these drugs represent the first examples of rational, computer-assisted, receptor-based inhibitor design that have been approved for human use. Their design required a careful balance of antiviral activity, lipophilicity, solubility and pharmacokinetic characteristics [15], [16], [17], [18], [19]. The role of pharmacokinetics in the discovery and development of the HIV protease inhibitors is discussed in a recent review by Lin [8].
Although protease inhibitor therapy is highly effective, these drugs are characterized by low or variable bioavailability with limited penetration into the central nervous system (CNS) [2]. The recovery of replication-competent virus in CD4+ T cells after the long-term reduction of plasma virus to undetectable levels supports the concept of ‘pharmacological sanctuaries’ that resist antiviral therapy due to sub-therapeutic drug concentrations [20]. Since antiviral therapy requires high and prolonged plasma and tissue drug levels, low level viral reproduction could occur under subtherapeutic concentrations facilitating the development of resistant viral strains. Only free (unbound) drug is available to penetrate into tissues and to exert an antiviral effect; thus, the development of several HIV protease inhibitors has been discontinued due to extensive plasma protein binding or poor pharmacokinetic characteristics [8], [21], [22], [23].
Clinical use of the HIV protease inhibitors is limited by patient compliance and by drug–drug interactions. Drug–drug interactions are exacerbated by complicated dosage regimens that include multiple antiviral medications and the co-administration of other drug therapies. This review provides an overview while considering the relationships between hepatic and intestinal metabolism, and the low bioavailability, variable absorption and drug–drug interactions of the HIV protease inhibitors.
Section snippets
Physicochemical properties
The available physicochemical data for the HIV protease inhibitors are contained in Table 1. These drugs are structurally related, have higher molecular weights than traditional ‘small molecules’ and are highly lipophilic as demonstrated by their log P(o/w) values. Also important is their common pH-dependent solubility. In general, these drugs are soluble at low pH and poorly soluble at physiological pH (7.4). These solubility characteristics are consistent with the formation of protonated,
Absorption and pharmacokinetics
Table 2 contains a summary of the current dosing regimens and human pharmacokinetic parameters for each HIV protease inhibitor. It is difficult to make direct comparisons between these data because they are not all reported for the same conditions (e.g. single dose vs. steady state, fasted vs. fed vs. meal type, healthy vs. HIV patients); however, they are useful in illustrating some key points.
Although HIV protease inhibitor therapy is highly effective, these drugs are characterized by low or
First pass metabolism and elimination
One of the most important factors influencing the oral bioavailability of the HIV protease inhibitors is first pass metabolism. Prior to reaching systemic circulation, orally administered drugs must first pass through the intestine and then the liver; thus, the intestine and liver may both contribute to pre-systemic extraction. Drugs that experience high first pass metabolism often have systemic drug levels with high intersubject variability resulting from variation in the expression levels or
Efflux
Several recent reports suggest that secretory transport may contribute significantly to reduce the oral bioavailability of the HIV protease inhibitors. Drug secretion, in the form of multidrug resistance (MDR) was first encountered during the study of clinical resistance to hydrophobic chemotherapeutic agents used in cancer treatment [87]. MDR can be defined as the ability of cells exposed to a single cytotoxic agent to develop resistance to a broad range of structurally and functionally
Interactions between intestinal P-glycoprotein and intestinal CYP3A4
The potential interaction between intestinal Pgp and CYP3A4 may be an additional source of variation associated with HIV protease inhibitor absorption and distribution. In normal tissues, it is hypothesized that Pgp and CYP3A4 are functionally linked components of the xenobiotic detoxification cascade, limiting the bioavailability of a large number of drug substances [60], [66]. For example, in a 25-patient study, the combined variation in intestinal Pgp and hepatic CYP3A4 activity accounted
Drug–drug interactions
This section briefly reviews some of the common factors associated with HIV protease inhibitor drug–drug interactions. Since the HIV protease inhibitors are CYP3A4 and Pgp substrates, the bioavailabilities of the HIV protease inhibitors will be influenced by drugs inducing or inhibiting CYP3A4 and may be influenced by substances interacting with Pgp. Detailed clinical comparisons of HIV protease inhibitor drug–drug interactions are contained in a number of reviews on the subject [1], [2], [3],
Opportunities for improved therapy
In broad terms, improved therapy consists of improved efficacy with simplified patient compliance. Relative to the HIV protease inhibitors, improved therapy would include some of the following components:
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increased systemic oral bioavailability;
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reduced variation in bioavailability;
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reduced drug–drug interactions;
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reduced variation in drug–drug interactions.
To improve oral HIV protease inhibitor therapy, it is essential to mechanistically characterize the cell-specific, tissue-specific and regional
Acknowledgements
We gratefully acknowledge the support of Roche Laboratories, Abbott Laboratories and Glaxo Wellcome. Partial support for our work was provided by NIH grant AI33789 and AI42007.
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