Data presented at the Fourth Conference on Retroviruses and Opportunistic
Infections showed that the blood-brain barrier permeability of nevirapine
(Viramune) is superior to that of other antiretrovirals in both in vitro
and in vivo animal models.
"A critical issue in the treatment of HIV disease is the concern
about reaching virus residing in difficult-to-reach sanctuaries, such as
the brain," said Dr. Maureen Myers, Clinical Program Director of Virology
at Boehringer Ingelheim Pharmaceuticals, Inc. "We now have new evidence
that the pharmacologic properties of Viramune make it an attractive candidate
for studying antiretroviral effects on CNS [central nervous system] viral
The new studies looked at how well HIV agents penetrate the blood-brain
barrier, which may determine the success of attaining adequate drug levels
in the human brain and CNS, long thought to be reservoirs of HIV. The in
vitro model utilized bovine brain microvessel endothelial cells to study
and 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 permeable
than zidovudine and indinavir, respectively. Delavirdine was the only drug
that appeared not to cross the barrier. The in vitro results were supported
by in vivo data derived from the administration of the four antiretrovirals
to rats and/or monkeys. Neither indinavir nor delavirdine was found in
rat brain at concentrations of 1% of the simultaneous concentrations in
plasma. Similarly, published data show that zidovudine concentrations in
rat brain reach only 10% of plasma concentrations.
These results for nevirapine are consistent with the findings of a previous
study in humans in which the drug was found to be present in cerebrospinal
fluid (CSF) in concentrations approximately equal to the fraction not bound
to 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 possible
to achieve inhibitory antiretroviral concentrations of Viramune in the
brain where it may inhibit viral replication of HIV-1, potentially increasing
its 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 Pharmacokinetics
at Boehringer Ingelheim. "This is exciting in that it may provide
physicians with a drug that appears to reach one of the most protected
areas of the body in an effort to reduce total viral burden."