Data presented at the Fourth Conference on Retroviruses and Opportunistic Infections showed that the blood-brain barrier permeability of nevirapine(Drug information on 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 load."
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(Drug information on zidovudine) (Retrovir), indinavir(Drug information on 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."
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