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PK Goals Met With 90-Day TFV/LNG
Vaginal Ring in 47-Woman Randomized Trial
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HIVR4P Virtual, January 27-28 and February 3-4, 2021
Mark Mascolini
A 90-day trial randomizing women to continuous use of a tenofovir/levonorgestrel (TFV/LNG) intravaginal ring, to interrupted use (28 days in/2 out), or to continuous or interrupted placebo found that both TFV/LNG ring groups met drug concentration (pharmacokinetic, PK) goals [1]. This trial in the United States and the Dominican Republic found the ring generally safe and acceptable.
CONRAD group researchers already reported results of CONRAD 128, a phase 1, double-blind, placebo-controlled trial of this ring worn for approximately 15 days by healthy women [2,3]. The ring delivers 8 to 10 mg of TFV daily when loaded with TFV alone, or 20 ug of TFV daily when also loaded with LNG. This 50-woman trial found estimated TFV and LNG release rates within expected ranges, with sustained high local concentrations of TFV [2]. Drug-loaded rings did not differ from placebo rings in their effect on the vaginal microbiota [3].
The new trial, CONRAD 138, aimed to assess the safety, menstrual patterns, acceptability, pharmacokinetics, and pharmacodynamics of the same ring, versus a placebo ring, worn for 90 days. With sites at the Eastern Virginia Medical School and Clinica Profamilia in Santo Domingo, the trial enrolled healthy 18- to 50-year-old women without HIV of another sexually transmitted infection or use of exogenous hormones. Women had regular menstrual cycles and a body mass index below 30 kg/m2 (the obesity threshold).
Researchers randomized 19 women to continuous 90-day use of the TFV/LNG ring, 5 to a continuous placebo ring, 18 to interrupted TFV/LNG (28 days in/2 days out), and 5 to interrupted placebo. Women made about 32 visits and one follow-up call over 5 to 6 months. Five women (26%) withdrew from the continuous TFV/LNG arm, 2 (11%) from the interrupted TFV/LNG arm, and none from the placebo arms. Participant decision explained 4 of 7 withdrawals.
There were no serious adverse events and no genital ulcers. Treatment-emergent adverse events proved similar across study arms, most such events were mild or moderate, and no grade 3 treatment-emergent events were considered related to study treatment. Through 90 days of ring use, there were no statistically significant changes in ectocervical tissue histology, density or phenotype of ectocervical lymphocytes, or secreted soluble proteins from cervicovaginal mucosa.
With either continuous or interrupted TFV/LNG ring use, about 40% of women reported no change in menstrual cycle after 1 month or at the end of treatment. In the placebo group, 50% to 60% reported no change in menstrual cycle at these points.
TFV concentrations in vaginal fluid reached a 1000-ng/mg target at 48 hours and stayed at that level or higher through day 84, the end of treatment. In vaginal tissue, concentrations of TFV-DP, the active form of tenofovir, climbed from just above 100 fmol/mg 24 hours after ring insertion to above 1000 fmol/mg at 72 hours. Concentrations remained above 100 fmol/mg 48 hours, 72 hours, and 5 days after ring removal.
LNG concentrations lay at or above a target of 200 pg/mL at days 1-3, month 1, month 2, and month 3, then fell below 100 pg/mL 48 hours after final ring removal. All women who used a TFV/LNG ring had at least one surrogate of contraceptive efficacy during treatment: cervical mucus Insler score, sperm migration assay, and monthly ovulation by serum progesterone. All women using placebo rings ovulated monthly. After 1 and 3 months of ring use, vaginal fluid of women using the TFV/LNG ring had significantly greater HIV inhibitory activity in vitro compared with baseline or placebo (P < 0.01)
The CONRAD team concluded that both TFV and LNG met concentration benchmarks in this 90-day trial. They found that both HIV pharmacodynamic models and LNG pharmacodynamic surrogates support activity of these two agents delivered by this intravaginal ring. Four clinical trials of this TFV/LNG ring are now completed, including one in Kenya, and further clinical study is planned.
References
1. Thurman AR, Brache V, Quattara A, et al. Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of a multipurpose prevention vaginal ring containing tenofovir and levonorgestrel. HIVR4P (HIV Research for Prevention) Virtual, January 27-28 and February 3-4, 2021. Abstract OA06.02.
2. Thurman AR, Schwartz JL, Brache V, et al. Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. PLoS One. 2018;13:e0199778. doi: 10.1371/journal.pone.0199778. https://pubmed.ncbi.nlm.nih.gov/29953547/
3. Thurman AR, Schwartz JL, Ravel J, et al. Vaginal microbiota and mucosal pharmacokinetics of tenofovir in healthy women using tenofovir and tenofovir/levonorgestrel vaginal rings. PLoS One. 2019;14:e0217229. doi: 10.1371/journal.pone.0217229. https://pubmed.ncbi.nlm.nih.gov/31107913/
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