Ocular and Cerebrospinal Fluid Penetration of Antiretroviral Agents

The ocular penetration of systemically administered antiretroviral drugs (ARVs), which is important in the clinical setting of HIV uveitis, is unknown. This study aimed to assess the ocular penetration of different antiretroviral drugs in an animal model.

Twenty-five male New Zealand white rabbits were assigned to one of five treatment groups. Each group received a single oral dose of an antiretroviral drug (lamivudine, tenofovir, efavirenz, lopinavir, and raltegravir). These 5 drugs represent 4 different ARV drug classes [nucleoside reverse transcriptase inhibitors (NRTI), non-NRTI, protease inhibitors, and integrase inhibitors]. Serum, cerebrospinal fluid (CSF), and aqueous and vitreous humor samples were collected at the time of theoretical maximum serum concentration of each respective drug, for example, lamivudine 1 h, tenofovir 1 h, efavirenz 5 h, lopinavir 4 h, and raltegravir 3 h. The drug concentration in each sample was determined by means of high-performance liquid chromatography and mass spectrometry.

After a single oral dose, measurable levels of all five ARVs administered could be detected in all 4 body compartments. The limit of detection based on a signal-to-noise ratio of 1:3 for the antiretroviral agents was as follows: 1 part per billion (ppb) for lamivudine, tenofovir, and efavirenz and 0.1 ppb for lopinavir and raltegravir. The IC50 (inhibitory concentration where 50% of viral replication is inhibited by a drug) was reached for all drugs in the serum and CSF. In the aqueous humor, lopinavir failed to reach IC50 and in the vitreous humor, only efavirenz and lopinavir attained IC50 levels.

After a single oral dose, measurable levels of all 4 classes of ARVs could be detected in all 4 body compartments sampled. In the eye, IC50 levels were lower in the vitreous humor than in aqueous humor. IC50 levels in the serum were higher than in the CSF.