Vaginal Microbicide Provides 24-Hour Protection in Study

MONTREAL — A single application of a vaginal microbicide gel resulted in persistently protective levels 24 hours later, with no significant side effects, reported Dr. Katherine Bunge of Magee-Womens Hospital in Pittsburgh.

This preliminary safety and persistence information "justifies daily dosing," she said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

The phase I, single-center trial of the nonnucleoside reverse transcription inhibitor UC-781 randomized 60 healthy women at a ratio of 2:1 to either treatment or placebo, explained Dr. Bunge, who had no disclosures to declare.

The women (mean age 26 years) also were randomized to product exposure durations of either 2, 4, or 8 hours. They received a physician-administered dose of vaginal gel and were then required to stay in the research facility for their assigned time period, after which specimens were collected by cervicovaginal lavage (CVL) and vaginal swabs. The subjects then returned 1 day, 1 week, and 1 month later for follow-up.

Urogenital irritation was assessed by pelvic exam and symptoms, microscopic genital changes were assessed by colposcopy, systemic safety was assessed by history and laboratory parameters, vaginal flora was quantified, and cervical cytokines were measured.

"These are fairly typical safety measures in any phase I trial of a microbicide, but what we attempted to do that hadn't really been looked at before was to figure out a way to determine the persistence of this vaginally applied drug that we didn't really expect to be absorbed," she said.

To that end, plasma drug levels were measured both immediately after the patients' timed exposure and then again a day later; drug levels were measured in CVL and vaginal swab specimens, which also were collected at those two time points, Dr. Bunge explained.

At 24 hours post exposure, two patients had detectable levels of UC-781 in their plasma, but in both cases the levels were considered below the limits of quantification, she said.

In contrast, "the most important and interesting data" showed persistence of the drug in the vagina, she said. Eight hours after treatment, 100% of the women had detectable drug levels in CVL specimens and 90% had detectable levels in vaginal swab specimens. At 24 hours post exposure, 93% had detectable levels after a second CVL, and 42% showed detectable levels after a second vaginal swab.

Dr. Bunge pointed out that even after 24 hours, the median concentration of UC-781 in CVL specimens was 4,965 pmol/mL. "The inhibitory concentration of UC-781 is 2 pmol/mL, so in fact at 24 hours after washout, the median concentration of detectable drug in CVL samples was a thousand times the inhibitory concentration."

Among the 197 adverse events (121 in the treatment group and 76 in the placebo group), 85% were classified as mild. There were four severe events but all were deemed not related or probably not related to treatment, said Dr. Bunge.

"There was no difference between groups in terms of concentration of microorganisms at every time point, or proinflammatory cytokines—and most importantly in the treatment group, there was no shift in these concentrations," she said. A total of 18 patients had new colposcopic findings on follow-up, but all were considered superficial.

MONTREAL — A single application of a vaginal microbicide gel resulted in persistently protective levels 24 hours later, with no significant side effects, reported Dr. Katherine Bunge of Magee-Womens Hospital in Pittsburgh.

This preliminary safety and persistence information "justifies daily dosing," she said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

The phase I, single-center trial of the nonnucleoside reverse transcription inhibitor UC-781 randomized 60 healthy women at a ratio of 2:1 to either treatment or placebo, explained Dr. Bunge, who had no disclosures to declare.

The women (mean age 26 years) also were randomized to product exposure durations of either 2, 4, or 8 hours. They received a physician-administered dose of vaginal gel and were then required to stay in the research facility for their assigned time period, after which specimens were collected by cervicovaginal lavage (CVL) and vaginal swabs. The subjects then returned 1 day, 1 week, and 1 month later for follow-up.

Urogenital irritation was assessed by pelvic exam and symptoms, microscopic genital changes were assessed by colposcopy, systemic safety was assessed by history and laboratory parameters, vaginal flora was quantified, and cervical cytokines were measured.

"These are fairly typical safety measures in any phase I trial of a microbicide, but what we attempted to do that hadn't really been looked at before was to figure out a way to determine the persistence of this vaginally applied drug that we didn't really expect to be absorbed," she said.

To that end, plasma drug levels were measured both immediately after the patients' timed exposure and then again a day later; drug levels were measured in CVL and vaginal swab specimens, which also were collected at those two time points, Dr. Bunge explained.

At 24 hours post exposure, two patients had detectable levels of UC-781 in their plasma, but in both cases the levels were considered below the limits of quantification, she said.

In contrast, "the most important and interesting data" showed persistence of the drug in the vagina, she said. Eight hours after treatment, 100% of the women had detectable drug levels in CVL specimens and 90% had detectable levels in vaginal swab specimens. At 24 hours post exposure, 93% had detectable levels after a second CVL, and 42% showed detectable levels after a second vaginal swab.

Dr. Bunge pointed out that even after 24 hours, the median concentration of UC-781 in CVL specimens was 4,965 pmol/mL. "The inhibitory concentration of UC-781 is 2 pmol/mL, so in fact at 24 hours after washout, the median concentration of detectable drug in CVL samples was a thousand times the inhibitory concentration."

Among the 197 adverse events (121 in the treatment group and 76 in the placebo group), 85% were classified as mild. There were four severe events but all were deemed not related or probably not related to treatment, said Dr. Bunge.

"There was no difference between groups in terms of concentration of microorganisms at every time point, or proinflammatory cytokines—and most importantly in the treatment group, there was no shift in these concentrations," she said. A total of 18 patients had new colposcopic findings on follow-up, but all were considered superficial.

MONTREAL — A single application of a vaginal microbicide gel resulted in persistently protective levels 24 hours later, with no significant side effects, reported Dr. Katherine Bunge of Magee-Womens Hospital in Pittsburgh.

This preliminary safety and persistence information "justifies daily dosing," she said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

The phase I, single-center trial of the nonnucleoside reverse transcription inhibitor UC-781 randomized 60 healthy women at a ratio of 2:1 to either treatment or placebo, explained Dr. Bunge, who had no disclosures to declare.

The women (mean age 26 years) also were randomized to product exposure durations of either 2, 4, or 8 hours. They received a physician-administered dose of vaginal gel and were then required to stay in the research facility for their assigned time period, after which specimens were collected by cervicovaginal lavage (CVL) and vaginal swabs. The subjects then returned 1 day, 1 week, and 1 month later for follow-up.

Urogenital irritation was assessed by pelvic exam and symptoms, microscopic genital changes were assessed by colposcopy, systemic safety was assessed by history and laboratory parameters, vaginal flora was quantified, and cervical cytokines were measured.

"These are fairly typical safety measures in any phase I trial of a microbicide, but what we attempted to do that hadn't really been looked at before was to figure out a way to determine the persistence of this vaginally applied drug that we didn't really expect to be absorbed," she said.

To that end, plasma drug levels were measured both immediately after the patients' timed exposure and then again a day later; drug levels were measured in CVL and vaginal swab specimens, which also were collected at those two time points, Dr. Bunge explained.

At 24 hours post exposure, two patients had detectable levels of UC-781 in their plasma, but in both cases the levels were considered below the limits of quantification, she said.

In contrast, "the most important and interesting data" showed persistence of the drug in the vagina, she said. Eight hours after treatment, 100% of the women had detectable drug levels in CVL specimens and 90% had detectable levels in vaginal swab specimens. At 24 hours post exposure, 93% had detectable levels after a second CVL, and 42% showed detectable levels after a second vaginal swab.

Dr. Bunge pointed out that even after 24 hours, the median concentration of UC-781 in CVL specimens was 4,965 pmol/mL. "The inhibitory concentration of UC-781 is 2 pmol/mL, so in fact at 24 hours after washout, the median concentration of detectable drug in CVL samples was a thousand times the inhibitory concentration."

Among the 197 adverse events (121 in the treatment group and 76 in the placebo group), 85% were classified as mild. There were four severe events but all were deemed not related or probably not related to treatment, said Dr. Bunge.

"There was no difference between groups in terms of concentration of microorganisms at every time point, or proinflammatory cytokines—and most importantly in the treatment group, there was no shift in these concentrations," she said. A total of 18 patients had new colposcopic findings on follow-up, but all were considered superficial.