Measurement of Plasma and Intracellular Concentrations of Raltegravir

Integrase strand transfer inhibitors are one of the newest class of antiretroviral drugs.
This class of drugs inhibit the catalytic activity of HIV-1 integrase, an HIV-1-encoded
enzyme required for viral replication [1]. Inhibition of integrase prevents covalent
insertion of unintegrated, linear HIV-1 DNA into the host cell genome, therefore preventing
the formation of HIV-1 provirus. RAL, the first agent in its class, was initially approved in
2007 for use in patients harboring drug-resistant HIV [2]. More recently, the FDA has
expanded the indication for RAL use in HIV-infected patients who are antiretroviral naïve
[3]. The currently approved dose is 400 mg twice daily. The RAL area-under-the-curve (AUC)
and Cmax increase in a dose-dependent fashion over the range of 100 mg to 1,600 mg. With
twice-daily dosing, PK steady state is achieved within approximately the first 2 days.
Considerable variability was observed in the PK of raltegravir in clinical trials. In
clinical trial participants receiving twice-daily RAL 400 mg, drug exposures were
characterized by a geometric mean AUC within the first 12 hours of 14.3 mcM(hr) and a plasma
concentration at 12 hours of 142 nM [3]. RAL at concentrations of 6 to 50 nM resulted in 95%
inhibition (EC95) of viral spread in mitogen-activated human peripheral blood mononuclear
cells (PBMCs) infected with diverse, primary clinical isolates of HIV-1, including isolates
resistant to reverse transcriptase inhibitors and protease inhibitors (PIs).

The absolute bioavailability of RAL has not been established. RAL is approximately 83% bound
to human plasma protein over the concentration range of 2 to 10 mcM. The apparent terminal
half-life of RAL is approximately 9 hours, with a shorter alpha-phase half-life (about 1
hour), accounting for much of the AUC. Determination of drug levels to guide treatment of HIV
infection is available for protease inhibitors (PI) and non-nucleoside reverse transcriptase
inhibitors (NNRTI) but is not yet considered standard of care [4,5]. RAL is associated with
potent performance against HIV in treatment-naïve patients and those with limited treatment
options, potentially because of its binding interaction with the HIV preintegration complex.
When RAL binds to the complex, the drug dissociates at a rate slower than the half-life of
the complex itself, which makes binding essentially irreversible. Thus, the efficacy of RAL
may be dependent on intracellular binding levels of the drug to the preintegration complex,
rather than on the plasma concentrations of RAL. Because of this, we postulate that
intracellular concentrations of RAL are more likely to correlate with biological activity
against HIV. Moreover, if pharmacokinetic behavior can be predicted, and depending on the
trough concentrations observed, the drug might be suitable for different dosing approaches
including once a day administration. This would create more flexibility for patients, and the
chance to improve adherence.

Inclusion Criteria:

- Be of age greater than or equal to 19 years

- Have documented HIV

- Be taking RAL for at least 7 days

Exclusion Criteria:

- Any acute intercurrent illness that might interfere with the interpretation of the
study