Comparison of Concentration-time Course of Plasma and Intracellular Raltegravir in Healthy Volunteers

In less than 15 years, human immunodeficiency virus (HIV) infection has reached the level of a pandemic, and acquired immunodeficiency syndrome (AIDS) has been reported in over 190 countries. By the end of 2001, more than 30 million people were infected with HIV worldwide, with approximately one million of those infected residing in North America and one million residing in Europe.

Significant advances have been made in the treatment of HIV disease. The nucleoside reverse transcriptase inhibitors provided the earliest therapeutic intervention for HIV infection. This class of antiretroviral agents interferes with the replication of HIV by competitive inhibition of the HIV reverse transcriptase enzyme and by chain termination of new HIV DNA into which the nucleoside analogue has been incorporated. Subsequent development of other potent drug classes, such as non nucleoside reverse transcriptase inhibitors and protease inhibitors, has made possible the use of multidrug, multiclass regimens that can achieve durable suppression of HIV replication. However, extensive resistance has developed to these classes of drugs, necessitating the development of other potent classes of antiretroviral therapy.

The integrase inhibitors are a new class of antiretroviral drugs. They inhibit the catalytic activity of HIV integrase, an HIV encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome preventing the formation of the HIV provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection.

Raltegravir (RAL) is a newly approved HIV integrase inhibitor. It is approved in salvage regimens(Merck \&Co Inc. 2007) and shows promise in first line therapy. Raltegravir is potent in vitro; concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir at concentrations of 6 to 50 nM resulted in 95% inhibition of viral spread in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors.

RAL plasma concentrations are highly variable even after controlling for food intake and UGT1A1*28 polymorphisms. Despite this variability, RAL remains efficacious and studies have shown little correlation between various RAL pharmacokinetic parameters and efficacy(Wenning, Hwang et al. 2008). This suggests that although RAL exposure may be important, plasma concentrations may not the best marker of RAL exposure.

RAL exerts its effects in the HIV-infected cells where it inhibits the HIV integrase. Therefore intracellular concentrations should correlate with efficacy much more than plasma concentrations. It is possible that RAL could accumulate inside HIV-infected cells or that intracellular concentrations could be less variable, explaining the sustained efficacy of RAL despite variable plasma concentrations. Intracellular half-life could also be longer than the relatively short plasma half-life. This information could be used to justify once daily administration of RAL, just as zidovudine dosing was changed from five times to twice daily because intracellular zidovudine triphosphate had a much longer half-life than plasma zidovudine(Barry, Khoo et al. 1996).

Measurement of intracellular raltegravir could also aid in therapeutic drug monitoring and assessing drug-drug interactions. For example, rifampin reduces plasma concentration of RAL by almost 50%(Wenning, Hanley et al. 2009). However, dose increases may not be necessary if intracellular concentrations are maintained, as is thought to be true for zidovudine after rifampin co-administration.

To our knowledge, there has been no data on intracellular raltegravir. We therefore aim to measure the time course of RAL intracellular concentrations after a single dose in healthy volunteers.