A silicone intravaginal ring that releases the antiretroviral drugs dapivirine and darunavir was shown to reach levels expected to be effective in vaginal and cervical fluid and tissues in monkeys, researchers reported at the HIV Research for Prevention meeting last week in Cape Town. A related study found that a single ring can potentially serve multiple purposes, preventing HIV, genital herpes, HPV, and pregnancy.
Dapivirine + Darunavir
Diarmaid Murphy from Queen's University in Belfast reported pre-clinical data from the European CHAARM project, testing combinations of antiretroviral drugs that may be suitable for delivery in a vaginal ring for HIV prevention.
Combination vaginal rings containing 2 or more antiretrovirals targeting different steps in the HIV lifecycle may be more effective than single microbicides at preventing sexual transmission, the researchers noted as background. Several combination rings are already in development, most commonly dispensing the nucleotide reverse transcriptase inhibitor tenofovir -- approved, along with emtricitabine, for oral pre-exposure prophylaxis (PrEP) -- and the experimental NNRTI dapivirine (TMC120).
This analysis evaluated matrix type silicone elastomer rings that delivered dapivirine plus the protease inhibitor darunavir (marketed in oral form as Prezista). The rings were tested in vitro and in cynomolgus macaque monkeys.
A variety of rings were produced, containing 25 mg dapivirine, 100 mg dapivirine, 300 mg darunavir, and 100 mg dapivirine + 300 mg darunavir. The researchers tested release of the drugs in vitro and calculated the IC50, or concentration needed to inhibit viral replication by 50%, when vaginal fluid was exposed to HIV. They also measured concentrations of the drugs in macaques' blood serum, vaginal fluid, and vaginal, cervical, and other tissues over 28 days of using the rings.
In vitro release from the rings was dependent on drug loading, whether the rings contained 1 or 2 drugs, and the release medium. The melting temperature of dapivirine was reduced when combined with darunavir.
In monkeys, blood serum levels ranged from 20 to 300 pg/mL for both dapivirine and darunavir. Vaginal fluid levels ranged from 2000 to 200,000 ng/g for both drugs. Vaginal fluid levels were "well above" the IC50 for both dapivirine and darunavir
Looking at tissue concentrations, vaginal tissue drug levels ranged from 1000 to 5000 ng/g, while cervical tissue levels were 100 to 400 ng/g. Drug levels in uterus and rectal tissue, however, were substantially lower. This is an interesting contrast with other studies presented at the meeting showing that oral Truvada (tenofovir + emtricitabine) and injectable rilpivirine reach higher levels in rectal compared with vaginal tissue.
Based on these results -- and in light of progress in an ongoing clinical trial of a 25 mg dapivirine-only ring, the researchers concluded that a combination vaginal ring containing dapivirine plus darunavir "is a viable second-generation HIV microbicide candidate."
|Period||04 Nov 2014|