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Injected Rilpivirine for PrEP Stays in Plasma for 84 Days in Women and Men
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
A single 600-mg intramuscular dose of the nonnucleoside rilpivirine remained in the circulation for 84 days in 10 women and 6 men without HIV [1]. Vaginal tissues levels of rilpivirine were slightly lower than cervicovaginal fluid levels, whereas male rectal tissue rilpivirine concentrations were higher than rectal fluid levels. The findings suggest that intermittently injected rilpivirine could be effective pre-exposure prophylaxis (PrEP), if the concentrations maintained protect against HIV.
Studies of daily tenofovir/emtricitabine for PrEP showed that the strategy substantially lowers the risk of HIV acquisition in women and men, as long as the drugs are taken regularly [2-5]. In one trial high-risk African women randomized to take tenofovir/emtricitabine PrEP or placebo adhered poorly and were not protected from HIV [5]. Because rilpivirine has a long half-life, University of Liverpool and St. Stephen's Centre investigators planned this study to determine how long concentrations of a long-acting rilpivirine nanosuspension persist in plasma and genital compartments.
This open-label exploratory pharmacokinetic trial involved 10 women and 6 men without HIV infection and with a low behavioral HIV risk. Eight of the women were African in ancestry, 1 was white, and 1 was Asian. Five men where white and 1 African. Median ages were 37 in women and 40 in men.
Study participants received a single 600-mg shot of rilpivirine G001 long-acting nanosuspension in the gluteus maximus and had plasma samples collected regularly for the next 84 days. Study participants also routinely collected cervicovaginal fluid by direct aspiration or rectal fluid by intra-rectal aspiration with Weck Cel spears. Vaginal tissue biopsies were done 14 days or 7 and 28 days after the injection, and rectal tissue biopsies were done in men 7 and 14 days after the injection.
Rilpivirine concentrations persisted in plasma in women and men for 84 days at the following geometric mean (and 90% confidence interval) concentrations:
-- 84-day area under the concentration-time curve (AUC84d): 3673 ng*day/mL (3039-4307) in women and 4555 ng*day/mL (3720-5391) in men
-- Concentration on day 84 (C84d): 16.5 ng/mL (12.3-20.6) in women and 20.1 ng/mL (16.0-24.3) in men
-- Maximum concentration (Cmax): 98.4 ng/mL (81.6-115.2) in women and 131.7 ng/mL (102.5-160.8) in men
-- Time to maximum concentration: 6.9 days (2.1-11.9) in women and 4.6 days (3.4-5.7) in men
-- Terminal half-life: 35.3 days (24.4-41.4) in women and 32.9 days (24.4-41.4) in men
In women rilpivirine cervicovaginal fluid/plasma ratios were 1.21 (0.88-1.53) for AUC84d, 1.41 (0.91-1.91) for C84d, and 1.23 (0.86-1.60) for Cmax. Vaginal tissue/plasma ratios were 0.68 (0.53-0.84) on day 7, 0.75 (0.57-0.93) on day 14, and 1.09 (0.54-1.69) on day 28.
In men rilpivirine rectal fluid/plasma ratios were 0.21 (0.11-0.31) for AUC84d, 0.07 (0.03-0.17) for C84d, and 0.28 (0.19-0.36) for Cmax. Rectal tissue/plasma ratios were 0.92 (0.82-1.02) on day 7 and 0.89 (0.65-1.14) on day 14.
Rilpivirine concentrations were slightly lower in vaginal tissue than in cervicovaginal fluid (VT/CVF ratio 0.73-1.01), whereas in men concentrations were higher in rectal tissue than in rectal fluid (RT/RF ratio 3.88-6.32).
Summing up, for women rilpivirine accumulation was greatest in vaginal fluid followed by plasma, which was equivalent with vaginal tissue. In men rilpivirine accumulation was greatest in rectal tissue, followed by plasma, followed by rectal fluid. Overall, men had about 25% higher rilpivirine plasma exposure than women.
The Liverpool team noted that "further studies are required to determine the safety and pharmacokinetics of long-acting rilpivirine following multiple dosing and to determine whether the concentrations achieved at these transmission sites are adequate to prevent infection."
References
1. Else L, Jackson A, Tjia J, et al. Pharmacokinetics of long-acting rilpivirine in plasma, genital tract and rectum of HIV-negative females and males administered a single 600 mg dose. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_12.
2. Baeten J, Donnell D, Ndase P, et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 29.
3. Donnell D, Baeten J, C Hendrix C, et al. Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 30. http://www.natap.org/2012/CROI/croi_15.htm.
4. Anderson P, Liu A, Buchbinder S, et al. Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 31LB.
5. Van Damme L, Corneli A, Ahmed K, et al. The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 32LB. http://www.natap.org/2012/CROI/croi_19.htm.
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