The efficacy and toxicity of many drugs can be linked to the level of the drug achieved in the plasma, circulating cells and other body compartments. This has led some to suggest that we should be monitoring the amount of antiretroviral drug in a patient to then adjust the dose within an optimal range. This is referred to as therapeutic drug monitoring, or TDM.

Another approach would be to develop tests to predict drug levels based on genetic markers that could be done on an individual before he or she starts on treatment. This may help predict whether someone is prone to having unduly high drug levels, and who therefore may be more prone to toxicity. It may also help predict those who metabolize a drug more rapidly, and may thus require a higher dose of medication, or for whom another agent may be a better choice. Nevirapine (NVP, Viramune) would be an important drug to study in this regard, due to its association with severe side effects (i.e., hepatic toxicity and rash) and its low barrier to resistance, which could be made even lower by subtherapeutic drug levels. This work by Andrew Owen and his colleagues in Britain helps to shed some light on these issues at a population level.

An intriguing finding that Owen addresses is that nevirapine, despite penetrating all body compartments, curiously does not accumulate well in circulating mononuclear cells. As studied in 10 patients, it turns out that these cells are deficient in the organic anion transporting polypeptide (OATP) that is required for more efficient accumulation of nevirapine in these cells.

However, there are other ways nevirapine can get into cells, and/or be metabolized more rapidly or more slowly once it is in the cells. Additional work done in 35 individuals looked for single nucleotide polymorphisms (SNPs) that could explain the great variation that is observed in blood levels of nevirapine. First, a mutated form of P glycoprotein (Pgp) system (an enzyme in the membrane of the cell responsible for more efficient clearance of the drug by the cell) is clearly associated with higher drug levels. Two other SNPs of enzymes of the cytochrome P450 system (specifically CYP3A4 and CYP2D6) are also associated with higher drug levels. In fact, if an individual carries all 3 SNPs, drug levels can be increased 4-fold or more compared to what would be expected.

This is critical information with respect to our understanding of individual variability of drug levels and side effects in our patients. In a small study conducted in Malawi by Mina Hosseinipour,¹ nevirapine levels were uniformly higher than would be expected, a fact that could be explained (and could possibly have been predicted) by some of the genetic changes described above. Other researchers at Vanderbilt University^2,3 seemed to confirm an association between the SNPs described by Owen and the risk of nevirapine-associated hepatic toxicity. However, they also described other genetic changes that were not reported by Owen (in CYP2B6 and CYP3A5) that also seemed to correlate with drug toxicity, so we probably do not yet have a full picture of what is going on in vivo.

All of these data are important, and represent the first steps in the development of a clinical test that would predict who is at increased risk of higher nevirapine levels and increased toxicity, and in whom other therapeutic options should be considered.

Footnotes

1. Hosseinipour M, Corbett A, Kanyama C, et al. Pharmacokinetic comparison of generic and trade formulations of lamivudine, stavudine, and nevirapine in 12 HIV-infected Malawian subjects. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 631.

2. Ritchie M, Haas D, Motsinger A, et al. Genetic variation in drug transporter and metabolizing enzyme genes may be associated with non-nucleoside reverse transcriptase inhibitor hepatotoxicity. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 832.

3. Haas DW, Bartlett J, Andersen J, et al. Pharmacogenetics of nevirapine and hepatotoxicity: NWCS220, an ACTG collaborative study. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 833.