Viramune, New Antiretroviral Agent, Crosses the Blood-Brain Barrier

Data presented at the Fourth Conference on Retroviruses and OpportunisticInfections showed that the blood-brain barrier permeability of nevirapine(Viramune) is superior to that of other antiretrovirals in both in vitroand in vivo animal models.

"A critical issue in the treatment of HIV disease is the concernabout reaching virus residing in difficult-to-reach sanctuaries, such asthe brain," said Dr. Maureen Myers, Clinical Program Director of Virologyat Boehringer Ingelheim Pharmaceuticals, Inc. "We now have new evidencethat the pharmacologic properties of Viramune make it an attractive candidatefor studying antiretroviral effects on CNS [central nervous system] viralload."

The new studies looked at how well HIV agents penetrate the blood-brainbarrier, which may determine the success of attaining adequate drug levelsin the human brain and CNS, long thought to be reservoirs of HIV. The invitro model utilized bovine brain microvessel endothelial cells to studyand compare the ability of four antiretrovirals--nevirapine, zidovudine(Retrovir), indinavir, and delavirdine--to cross the blood-brain barrier.

In Vivo Data Support In Vitro Results

At 10- to 100-mcM concentrations, Viramune was 5 and 10 times more permeablethan zidovudine and indinavir, respectively. Delavirdine was the only drugthat appeared not to cross the barrier. The in vitro results were supportedby in vivo data derived from the administration of the four antiretroviralsto rats and/or monkeys. Neither indinavir nor delavirdine was found inrat brain at concentrations of 1% of the simultaneous concentrations inplasma. Similarly, published data show that zidovudine concentrations inrat brain reach only 10% of plasma concentrations.

These results for nevirapine are consistent with the findings of a previousstudy in humans in which the drug was found to be present in cerebrospinalfluid (CSF) in concentrations approximately equal to the fraction not boundto plasma proteins. Nevirapine is 60% protein bound (ie, 40% free drug).The six children tested had nevirapine levels in the CSF that were 45%(± 5%) of those in simultaneous plasma samples.

"Overall, these data support the contention that it may be possibleto achieve inhibitory antiretroviral concentrations of Viramune in thebrain where it may inhibit viral replication of HIV-1, potentially increasingits therapeutic value by reducing the total body viral burden. However,studies in humans are necessary to confirm this activity," said Dr.Susan Hattox, Associate Director of Drug Metabolism and Pharmacokineticsat Boehringer Ingelheim. "This is exciting in that it may providephysicians with a drug that appears to reach one of the most protectedareas of the body in an effort to reduce total viral burden."